BMC Medical Genomics
Review
Iron behaving badly: inappropriate iron chelation as a major
contributor to the aetiology of vascular and other progressive
inflammatory and degenerative diseases
Douglas B Kell*
Address: School of Chemistry and Manchester Interdisciplinary Biocentre, The University of Manchester, 131 Princess St, Manchester, M1 7DN, UK
E-mail: Douglas B Kell* - dbk@manchester.ac.uk
*Corresponding author
Published: 08 January 2009 Received: 2 September 2008
BMC Medical Genomics 2009, 2:2 doi: 10.1186/1755- 8794-2-2 Accepted: 8 January 2009
This article is available from: http://www.biomedcentral.com/1755-8794/2/2
© 2009 Kell; licensee BioMed Central Ltd.
This is an Open Access articl e distributed under t he te rms of the Creative Commons Attribution License (
http://creativecommons.org/license s/by/2.0),
which permits unre stricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
Abstract
Background: The production of peroxide and superox ide is an inevitable consequence of
aerobic metabolism, and while these particular 'reactive oxygen species' (ROSs) can exhibit a
number of biological effects, they are not of themselves excessively reactive and thus they are not
especially damaging at physiological concentrations. However, their reactions with poorly liganded
iron species can lead to the catalytic production of the very reactive and dangerous hydroxyl
radical, which is exceptionally damaging, and a major cause of chronic inflammation.
Review: We review the considerable and wide-ranging evidence for t he involvement of this
combination of (su)peroxide and poorly liganded iron in a large number of physiological and indeed
pathological processes and inflammatory disorders, especially those involving the progressive
degradation o f cellular and organismal performance. These diseases share a great many similarities
and thus might be considered to have a common cause (i.e. iron-catalysed free radical and especially
hydroxyl radical generation).
The studies reviewed include those focused on a series of cardiovascular, metabolic and
neurological diseases, where iron can be found at the si tes of plaques an d lesions, as well as studies
showing the significance of iron to aging and l ongevity. The effective chelation of iron by natural or
synthetic ligands is thus of major physiological (and potentially therapeutic) importance. As systems
properties, we need to recognise that physiological observables have multiple molecular causes,
and studying them in isolati on leads to inconsistentpatternsofapparentcausalitywhenitisthe
simultaneous combination of multiple factors that is responsible.
This explains, for instance, the decidedly mixed effects of antioxidants that have been observed,
since in some circumstances (especially the presence of poorly liganded iron) molecules that are
nominally antio xidants can actually act as pro-oxid ants. The reduction of redox stress thus re quires
suitable levels of both antioxidants and effective iron chelators. Some polyphenolic antioxidants
may serve both roles.
Understanding the exact speciation and ligand ing of iron in all its states is thus crucial to separating
its various pro- and anti-inflammatory activities. Redox stress, innate immunity and pro- (and some
anti-)inflammatory cytokines are linked in particular via signalling pathways involvi ng NF-kappaB
and p38, with the oxidative roles of iron here seemingly involved upstream of the IkappaB kinase
(IKK) reaction. In a number of cases it is p ossible to identify mechanisms by which ROSs and poorly
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liganded iron act synergi stical ly and autocatalytically, leadi ng to 'runaway' reactions that are hard to
control unless one tackles multiple sites of action simultaneously. Some molecules such as statins
and erythropoietin, not traditionally associated with anti-inflammatory activity, do indeed have
'pleiotropic' anti-inflammatory effects that may be of benefit here.
Conclusion: Overall we argue, by synthesising a widely dispersed literature, that the role of
poorly li ganded iron has been rather underappreciated in the past, and that in combination with
peroxide and superoxide its activity underpins the behaviour of a great many physiolo gical
processes that degrade over time. Understanding these requires an integrative, systems-level
approach that may lead to novel therapeutic targets.
Background a nd preamble
The 'balkanisation' of the literature is in part due to the
amount of it (some 25,000 journals with presently 2.5
million peer-reviewed papers per year, i.e. ~5 per
minute [1]), with a number http://www.nlm.nih.gov/
bsd/medline_cit_counts_yr_pub.html increas ing by
something approaching 2 per minute at PubMed/Med-
line alone. In addition, the disconnect between the
papers in the literature (usually as pdf files) and the
metadata describing them (author, journal, year, pages,
etc) is acute and badly needs filling [2]. Without solving
this problem, and without automation of the processes
of reading, interpreting and exploiting this literature and
its metadata in a digital format, we cannot make use of
the existing tools for text mi ning and natural language
processing (e.g. [3-5]), for joining disparate concepts [6],
for literature-based discovery (e.g. [7-11], and for studies
of bibliometrics [12, 13], literature dynamics [14],
knowledge domains [15], detecting republication [16]
and so on. Until we recognise these possibilities we are
unlikely to seek to realise them.
The present article (and see [17] for a preprint) serves to
show some of the benefits than can accrue from a more
overarching view of the otherwise highly disparate
literature in a particular domain (see also [18]), but
was done 'the h ard way', i.e. with a f ew bibl iographic
and bibliometric tools but without the kind of automa-
tion implied above. For the record, the main tools used
(see a review in [2]) were Web of Knowledge a nd Scopus
for literature and citation searching, supplemented by
Google Scholar. Some use was also made of ARROW-
SMITH [6, 19, 20] and GOPubMed [21], as well as
various workflows in t he Taverna environment [22-26],
includ ing the BioAID_DiseaseDiscovery workflow http://
www.myexperiment.org/workflows/72 writt en by Marco
Roos. Citations and attendant metadata were stored in
Endnote (latterly version X).
Introduction
Even under 'normal' conditions, as well as during
ischaemia when tissue oxygenation levels are low, the
redox poise of the mitochondrial respiratory chain is
such that the normally complete four-electron reduction
of dioxygen t o water is also accompanied by the
production, at considerable rates (ca 1–4% of O
2
reduced), of partially reduced forms of dioxygen such
as hydrogen peroxide and superoxide (e.g. [27-45]).
These 1- and 2-electron reductions of O
2
are necessarily
exacerbated when the redox poise of t he b-type
cytochromes is low, for instance when substrate supplies
are in ex cess o r w hen the terminal electron acceptor O
2
is
abnormally low due to hypoxia or ischaemia. Various
other oxygenases, oxidases and peroxidases can also lead
direct ly to the production of such 'reduc ed' forms of
dioxygen in vivo (e.g.[46-48]),withH
2
O
2
from xanthine
oxidase being especially implicated in ischaemia/reper-
fusion injury (e.g. [47, 49-54]). These molecules (per-
oxide and superoxide) can cause or contribute to various
kinds of oxidative stress. However, this is mainly not in
fact because they can react d irectly with tissue compo-
nents th em selves, since they a re
compar atively non-
toxic, cells have well-known means of dealing with them
[55], and they are even used in cellular signalling (e.g.
[56-60]). Much more importantly, it is because they can
react with other particular species to create far more
reactive and damaging products such as hydroxyl
radicals, with all these agents nevertheless being known
collectively (and indiscriminately) as reactive oxygen
species ( ROSs). Possibly the commonest means by
which such much more damaging species, in particular
the hydroxyl radical, are created is by reaction with
unliganded or incompletely liganded iron ions [61-63].
The themes of this r eview are thus (i) that it i s this
combination of poorly ligan ded iron spec ies, coupled to
the natural production of ROSs, that is especially
damaging, (ii) that the role of iron has received far less
attention than has the general concept of ROSs, albeit
the large literature that we review, and (iii) that this
basic combination underpins a great many (and often
similar) physiological chang es leading to a variety of
disease manifestations, and in particular those where
the development of the disease is manifestly progres-
sive and degenerative.
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An overview of the structure of the review is given in Fig 1, in
the form of a 'mind map' [64]. The main literature review for
this meta-analysis was completed on June 30
th
, 2008, with
some updates being added following the refereeing process.
Some relevant chemistry of iron and
reduced forms of oxygen
While superoxide and peroxide are the proximate forms
of incomplete O
2
reduction in biology, a reaction
catalysed by the enzyme superoxide dismutase [65]
serves to equilibrate superoxide and peroxide:
2O
2
•-
+2H
+
Æ H
2
O
2
+O
2
(1)
Arguably the most important reaction of hydrogen
peroxide with (free or poorly liganded) Fe(II) is the
Fenton reaction [66], leading to the very reactive and
damaging hydroxyl radical (OH
•
)
Fe(II) + H
2
O
2
Æ Fe(III) + OH
-
+OH
•
(2)
Superoxide can also react with ferric iron in the Haber-
Weiss reaction [67] to produce Fe(II) again, thereby
effecting redox cycling:
O
2
•-
+ Fe(III) Æ O
2
+ Fe(II) (3)
Figure 1
An overview of this article, set out in the f orm of a 'mind map' [64].
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Ascorbate can replace O
2
•-
within the cell for reducing
the Fe(III) to Fe(II) [68]. F urther reactions, that are not
the real focus here, follow from the ability of hydroxyl
radicals and indeed Fe(n) directly to interact with many
biological macro- and small molecules, especially
including DNA, proteins and unsaturated lipids. Thus
[69-73], Fe(II) and certain Fe(II) chelates react w ith lipid
hydroperoxides (ROOH), as they do with hydrogen
peroxide, splitting the O–O bond. This gives RO
•
,an
alkoxyl radical, which can also abstract H
•
from
polyunsaturated fatty acids and from hydroperoxides.
The resulting peroxyl radicals ROO
•
can continue
propagation of lipid peroxidation. Oxidative stress also
leads to considerable DNA damage [74-76] and to the
polymerisation and denaturation of proteins [77-79]
and proteolipids that can together form insoluble
structures typically known as lipofucsin (see e.g. [80,
81]) or indeed plaques. Such plaques can also entrap the
catalysts of their formation, and thereby point them up.
Some of the evidence for these is described below. Many
small molecule metabolic markers for this kind of
oxidative stress induced by the hydroxyl r adical and
other 'reactive oxygen species' (ROSs) are known [ 43,
82-89], and include 8-oxo-guanine [90-94], 8-hydroxy
guanine [95], 8-hydroxy-2'-deox y-guanosine [96, 97],
8-oxo-GTP [98 ], 4-hydroxy-2-hexenal [99], 4-hydroxy-
nonenal [100], 4-hydroperoxy-2-nonenal, various iso-
prostanes [101-107], 7-keto- cholesterol [108], many
other cholesterol derivatives [109], malondialdehyde
[110], neopterin [111], nitrotyrosine [112-115] and
thymidine glycol [116, 117]. Note that the trivial
names in common use for this kind of metabolite are
not helpful and may even be ambiguous or misleading,
and it is desirable (e.g. [118]) to refer to such molecules
using terminology that relates th em either to molecules
identified in persistent curated datbases [119] such as
ChEBI [120] or KEGG [121], or better to describe t hem
via database-independent encodings such as SMILES
[122] or InChI [123-128] strings. (There are other
oxidative markers that may be less direct, such as the
ratio of 6-keto-prostaglandin F1a to thromboxane B2
[129], but these are not our focus here.)
Overall, it i s in fact well e stablis hed that the interactions
between 'iron' sensu lato and partly reduced forms of
oxygen can lead to the production of the very damaging
hydroxyl radical (e.g. [43, 1 30-139]), and that this
radical in particular probably underpins or mediates
many higher-level manifestations of tissue damage,
disease, organ failure and ultimately death [36, 137,
140-143]. While the role of ROSs generally in these
processes has been widely discussed, the general
recognition of the impor tance of inadequately liganded
iron in each of them has perhaps been less than fully
appreciated. One of our tas ks here will therefore be to
stress this role of 'iron', and to assess the various means
of chelating 'iron' such that it does not in fact do this.
(Throughout we use 'iron' to refer to forms of Fe(n,
n > 0) with unspecified ligan ds, though we absolutely
stress that it is the
exact speciation and liganding that
determines the reactivity of 'iron' in catalysing r eactions
such as that of hydroxyl radical formation, and indeed its
bioavailability generally – inadequate liganding of iron
in the r equired forms can be a cause of anaemia even if
the total amount of 'iron' is plentiful.)
For completeness we note the reactions catalysed by
superoxide dismutase
2O
2
•-
+2H
+
Æ O
2
+H
2
O
2
(4)
and by catalase
H
2
O
2
Æ H
2
O+1/2O
2
(5)
These to gether, were th eir activi ty in the relevant
locations sufficiently gr eat, might serve to remove (su)
peroxide from cells completely.
In addition to reactive oxygen species there are ions such
as the perferryl ion (Fe-O) [144] and reactive nitrogen
species [ 60, 145-147]. These latter are mainly formed
from the natural radical NO, an important inflammatory
mediator [148], with peroxynitrite production (from the
reaction of NO and superoxide) [46, 149-154] leading to
nitrotyrosine [112], or nitro-fatty acid [155, 156] or
protein cystein nitrosylation [157, 158 ] being a common
means of t heir detection downstream. Other toxic
products of the reactions of NO include NO
2
,N
2
O
3
,
and S-nitrosothiols [159], and the sequelae of some of
these may also involve iron [160].
Overall, we recognise that these kinds of inflammatory,
oxidative stress-related reactions are accumulative and
somewhat irre versible [161], that they are consequently
age-related, and (see [162-165] and later), and that most
diseases and causes of mortality that are prevalent in the
developed world are in this sense largely manifestations
of this kind of aging.
Ligands and siderophores
As well as the reactions described above, ferrous ions will
react with oxygen under aerobic conditions to produce
ferric ions, and in natural environments there is little to
stop this. Consequen tly, and because these reflect
fundamental physicochemical properties of such ions,
the problems of both solubility and toxicity were faced
by bacteria (and indeed fungi [166-169]) long ago in
evolution, and were solved by their creation and
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excretion of (mainly ferric-)iron chelators known as
siderophores [170-189] (and for haemophores see
[190]). These typically have extremely tight binding
constants (K
f
>10
30
[191]) and can solubilise and
sequester iron such that it can be internalised via suitable
transporter molecules within the bacterial plasma
membrane [192]. Bacterial and fungal siderophores
usually form hexadentate o ctahedral complexes with
ferric iron and typical ly employ hydroxamates, a-
hydroxycarboxylates and catechols as extremely effective
Fe
3+
ligands [182]. Since bacterial growth requires iron,
it is unsurprising that siderophores are effectively
virulence factors ( e.g. [174, 193-196]). While upwards
of 500 microbial siderophores have been identified
[182], with new ones still appearing (some via genomic
analyses, e.g. [197]), and with the most common one in
medical use, desfer riox amine or DFO, being such a
bacterial product (see below), it is an astonishing fact
that no human siderophore has been chemically
identified, even though such activities were dete cted
nearly 30 years ago [198, 199 ] (see also [200- 205]). As
noted by Kaplan [206], "a discovery that m ammals
produce siderophores would lead to an epochal change
in the parad igm of mammalian iron ho meos tasis." To
this end, some recent events have begun to change
matters, and our overall knowledge of the regulation of
iron metabolism, considerably.
Mammalian iron metabolism
The total body iron in an adult male is 3000 to 4000 mg
and the daily iron requirement for erythropoiesis, the
major 'sink', is about 20 mg [207]. However, the loss of
iron in a typical adult male is very small [208, 209] and
can be met by absorbing just 1 – 2mgofironperday
[210, 211]. The care ful conservation and recycling of
iron – mainly from degrading erythrocytes – is in fact
essential because typical human diets contain just
enough iron to replace the small losses, although when
dietary iron is more abundant, absorption must be (and
is) attenuated s ince higher levels than necessary lead to
iron overload and many distressing sequelae contingent
on the radical production described above.
A variety of aspects of mammalian iron metabolism have
been reviewed in detail elsewhere (e.g. [134, 139, 195,
212-241]), including a series on 'iron imports'
[242-248], and for our present purposes ( Fig 2) mainly
involves the intestinal (mainly duodenal) uptake of Fe
(II) (produced from Fe(III) using a luminal ferrireduc-
tase) via a divalent metal ion transporter DMT1/DCT1/
NRAMP [249, 250] and its subsequent binding as Fe(III)
to transferrin (Tf). The intestinal uptake of haem (heme)
occurs via th e heme carrier protein-1 (HCP1) [251] and
it is thereby internalized, while the iron in heme is
liberated by heme oxygenase-1 ( HO1) [25 2-254]. Haem
is synthesised in many tissues, e specially liver and
erythroid cells [255]. Vesicular routes of intestinal
transfer may also occur [25 6, 257]. Low MW cytoplasmic
chelators such as citrate can bind iron fairl y weakly and
thereby contribute to a labile iron pool (LIP) in the
cytoplasm and especially the lysosomes and mitochon-
dria (see [258-262]), while ferritin [263] too can bind
cytoplasmic iron (via a chaperone [264]) and is seen as a
good overall marker of iron status [265-267]. Iron(II) is
subsequently exported through the basolateral mem-
brane of the enterocyte by ferroportin-1 (FPN1)
[268-270]. Ferroportin may also contribute to uptake
in enterocytes [271]. Fe(III) may then be produced by
hephaestin (Hp) [272] before it is bound by transferrin
(Tf), which is the main but not sole means of binding Fe
(III) when it is transported through the circulation, with
major iron storage taking place in the liver. Similar
processes occur in t he peripheral tissues, with significant
transfer of iron from transferrin occurring via t he
transferrin receptor [273].
'Free' haem appears in the circulation (it may have a
signalling role [274]) and elsewhere largely because of
erythrocyte degradation, and it can also greatly amplify
the ce llular damage caused by ROSs [ 275], and its
degradation pathway via haem oxygenase [276, 277] to
biliverdin and then using biliverdin reductase to form
bilirubin generates 'free' (and potentially redox-active)
iron. It would appear, not least because biliverdin has
powerful antioxidant properties, that haem oxygenase is
more protective than damaging [253, 278-282], even
though one of the products of its reaction is Fe that must
eventually be liganded (or e.g. incorporated into
Figure 2
Schematic overview of the main elements considered
to participate in mammalian iron metabolism.
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ferritin). (Another product is the gas CO, that has been
proposed as a measure of oxidative stress in the lung
[283].)
All of the above obviously ignores both some important
aspects of the speciation and liganding of iron, as well as
the tissue distribution of the specific proteins involved –
for which latter global information will shortly emerge
[284] (http://ww w.proteinatlas.org/ and see later). It
also ignores any discussion on the genetic regulation of
iron metabolism (e.g. [285-288]), which is not our main
focus.
However, one molecule in particular, hepcidin, has
recently emerged as a 'master regulator' of regulation at
the physiological level, and we describe some of these
new developments.
Hepcidin
In the liver and elsewhere, many aspects of iron
metabolism are regulated by a recently discovered 25-
amino acid polypeptide called hepcidin [207, 241, 245,
271, 289-327] that acts in part as a negative regulator of
iron efflux [328] by causing the internalisation of
ferroportin [329-333]. Hepcidin is produced, partly
under the regulation of a receptor called hemojuvelin
(e.g. [334]), via an 84-aa precursor called pre-pro-
hepcidin and a 6 0 mer called pro-hepcidin [304, 335,
336] although the active agent is considered to be the 25
mer referred to above, and with the inactive precursors
appearing not to be useful markers [337, 338].
Strikingly, anaemia and anoxia both suppress hepcidin
production [245, 339, 340] (Fig 3), such that just while
superoxide production is being enhanced by the anoxia
there is more iron being absorbed from the intestine and
effluxed int o the circulation. In view of the inter-
reactivity of superoxide and iron this could be antici-
pated to enhance free radical formation, leading to a
positive feedback loop in which the problems are
amplified: ischaemia/anoxia changes Fe(n) distribution
leading to differential reactivity with the products of
anoxia and thus further free radical production. How-
ever, hepcidin is overexpressed in inflammatory disease
and is an early inflammatory marker [245, 341-3 45]. Its
expression is positively controlled inter alia by SMAD4,
and loss of hepatic SMAD4 is thus associated with
dramatically decreased expression of hepcidin in liver
and increased duodenal expression of a variety of genes
involved in intestinal iron absorption, including Dcytb,
DMT1 and ferroportin, leading to iron overload [346].
STAT3 is another positive effector of hepcidin expression
[347, 348], and ROSs inhibit this effect [349], thereby
creating a link between ROSs and Fe metabolism. To
understand the exact roles of hepcidin in iron metabo-
lism, it is going to be especially important to understand
where it is expressed; f ortunately, such studies are
beginning to emerge [350].
Overall there is a c omplex interplay b etween positive
and negative regulation and the organismal distribution
of iron caused by changes in hepcidin concentration
[351], with in many cases the hypoxic response
(decreased hepcidin) seeming to dominate that due to
inflammation (increased hepcidin ) even when iron
levels are high [35 2, 353]. Specifically, lowered hepcidin
causes hyperferraemia. Hepcidin is also activated by p53
[354], and may play a rol e in the degradation of
atherosclerotic plaques [355]. Another recently discov-
ered protein that is crucially involved in human iron
metabolism is NGAL or siderocalin, and while there is
some evidence for their co-regulation [356], they have
normally been studied separately.
NGAL (also known as lipocalin-2 or siderocalin)
Lipocalins [357] are a diverse group of ligand-binding
proteins that share a conserved structure even in the
absence of significant sequence conservation. This core
structure includes an eight-stranded anti- parallel b
barrel that defines a calyx, or cup-shaped structure,
enclosing the ligand binding site.
NGAL – neutrophil gelatinase-associated l ipocalin – is a
21 kDal glycoprotein first isolated by Kjeldsen and
colleagues in 1993 [358]. Synonyms i nclude lipocalin 2,
siderocalin, Lcn2, a2-microglobulin-related protein or
neu-related lipocalin (in rats) [359, 360] and (in m ice)
Figure 3
Some effects of hepcidin, summarizing the fact that
hypoxic condition can suppress it and thus lead to
hyperferraemia. Since hypoxic conditions can also lead to
ROS production t he hypoxia-mediated regulati on of hepcidin
can have especially d amaging effects.
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24p3 or uterocalin [361]. Although lipocalins are well
knowntobeinvolvedinthesequestrationandtransport
of a variety of ligands, the natural ligand of NGAL (as is
the case with many lipocalins) was not initially known
even in terms of its chemical class. This changed with the
seminal paper of Goetz and colleagues [362] (and see
[206]) who purifie d recombinant NGAL from a parti-
cular strain of E. coli and found that its structure
contained a negativel y charged f erric siderophore with
a subnanomolar dissociation constant that it had
extracted from its bacterial host, and that the apo form
of this molecule could also act as a potent bacteriostatic
agent by sequestering iron (see also [3 63-367]). A
companion paper [368] showed that the iron-delivering
activity was expressed in mammalian cells. The structure
of NGAL is now known [369] and one of its interaction
partners is a matrix metalloproteinase [370] to which it
can presumably donate a met al ion and in the complex
decrease its degradation [371 ].
The findi ng that NGAL was one of the most highly
expressed proteins following ischaemia-reperfusion
injury in kidney cells [ 372-374], and prognostic of
kidney damage long before the more traditional marker
creatinine was raised significantly, has led to consider-
able i nteres t in this protein, especially as a marker of
renal injury [375-389], and perhaps as a therapeutic
[375]. Devireddy and colleagues [390] identified a
receptor that internalizes 24p3, and internalization of
iron bound to 24p3 prevents apoptosis. In contrast,
internalization of the apo form of 24p3 that does not
contain iron led to cellular iron efflux and apoptosis via
the proapoptotic protein Bim [391]. In humans the
megalin receptor can bind siderocalin (and its side-
rophore payload) and mediate its intracellular uptake
[392]. Oxidative stress can also induce its expression
[393], and it is protective against i t [394].
Exogenously administered NGAL also markedly upregu-
lates heme oxygenase-1, a proven multifunctional
protective agent in experimental Acute Kidney Injury
(AKI) that is thought to work by limiting iron uptake,
promoting intracellular iron release, enhancing produc-
tion of antioxidants such as biliverdin and carbon
monoxide, and inducing the cell cycle regulatory protein
p21 [279, 395, 396]. Because of this multifaceted
protective action, NGAL has emerged as a prime
therapeutic target in ischaemic AKI [379].
Structural and direct binding studies have suggested that
siderocalin tends (although not exclusively) to bind
catecholate-type ligands, rather than hydroxama te- or
carboxylate-based siderophores, at least when tested with
microbially derived siderophores [362, 363, 365] (but cf.
[369] for claims, disputed [360] and not now accepted, as to
the binding of bacterially derived formyl peptides!). The
role of NGAL, as a siderophore-binding agent, is thus
consistent with the widespread recognition that iron-
induced radical generation is intimately involved in a
variety of renal and other diseases [397, 398]. However,
while it is certainly the case that siderocalin can reduce the
virulence of bacteria when it binds the relevant bacterial
siderophores [362-367] and that bacteria can 'evade' this by
synthesising siderophores that siderocalin cannot bind (e.g.
[186, 187, 399-401]), it is questionable whether the only
role of siderocalin lies in fact in its antibacterial activity.
Rather we would suggest that its main role is in sequestrat-
ing iron via a human siderophore to stop inappropriately
liganded iron from producing damaging oxygen radicals.
Consistent with this iron-liganding role for human biology
is the fact that the tissue most highly expressing NGAL under
normal conditions is bone marrow [360, 402], the site of
erythropoiesis. The liganding can be extensive; as Goetz and
colleagues [362] note, "During inflammation, concentra-
tions of NGAL can increase to levels, with concentrations
approaching 20–30 nM in the serum [403], presumably
adequate to bind all available iron as ferric siderophore
complexes".
Significant changes in NGAL expression have also been
observed, for instance, during kinase-mediated signalling
[404, 405], in cardiovascular disease [406-409 ] and in
cancer [410-412].
These findings on the kidney and the role of NGAL,
together with the important knowledge that its chief
ligand is probably an unknown human siderophore
(Figs 2, 4), thus lead us to consider the role of this
Figure 4
Overview of the roles of ischaemia, ROSs, poorly
liganded iron and the iron metabolism regulators
HGAL and hepicidin in effecting inflammation as a
physiological level.
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system (and unliganded iron generally) in a whole series
of other diseases that all share many characteristics of
oxidative stress and inflammation (see also [413]). A
similar thesis, albeit with comparatively little stress on
iron, is the leitmotif of Finch's recent detailed monograph
[163]. The theme of these sections is thus to stress the
fact that while the role of ROSs in general in such
syndromes has been pointed up previously, that of iron
as a major culprit has not so generally yet been stressed,
notwithstanding that there is in fact a great deal of
pertinentliteraturethatweherehighlightasthefocusof
this review.
Some disease manifestations in which
iron may be implicated
Preeclampsia (PE)
Another important disease that shares many of the same
properties (or at least sequelae) of renal impairment,
and may have the same fundamental aetiology, is pre-
eclampsia. This is the most significant cause of morbidity
and m ortality in pregnant women [414]. The chief
clinical manifestations at time of diagnosis are a raised
blood pressure (hypertension) [415] and proteinuria,
together with raised creatinin e, co nsi stent with t he
reversible existence (since it is rel ieved upon delivery of
the baby) of rena l impairm ent. How ever, prognosti c
markers that might manifest early in pregnancy are
lacking, and would be highly desirable. There is wide-
spread agreement [416] that a poor connection of the
placenta to the uterus leads to ischaemia and thus
oxidative stress, with a substantial involvement of
apoptosis during the placental remodelling [417-423].
Since preeclampsia-like syndromes can be induced in
pregnant animals by surgical restriction of the uteropla-
cental blood supply [424], it is presumed that blood-
borne agents arising from the ischaemic placenta are the
cause of the generalized endothelial cell damage and
inflammatory responses that give rise to the symptoms
of hypertension, proteinuria, and sudden oedema
characteristic of preeclampsia [70]. Indeed, many studies
implicate oxidative stress as a substantial contributor to
this [425-489], while some have noted t he importance o f
iron status [70, 133, 450, 490-511], and so far as is
known the transporters of iron in the placenta are similar
tothoseinothercells[512].Oxidativestressofthistypeis
of course inflammatory in nature and inflammation is
observed in PE [472, 476, 484, 486, 513-519]. W e suggest
strongly that it is the
combination of inadequately
liganded Fe(II or III) and superoxide/peroxide leading
to OH
•
formation that is the chief mechanistic cause of
the downstream events that manifest in PE, and that
approp riat e removal by liganding/chel ation or otherwise
of these ions would prove of therapeutic benefit. (Iron
status has also been implic ated in other pregnancy and
neonatal disorders [520-524].) There is evidence too for
the involvement of the radical NO [456, 525].
We note that it is quite common nevertheless for iron to
be prescribed during pregnancy, especially during its
latter stages [526, 527], and t hat this does of course lead
to oxidative stress [ 528, 529].
Oxidative stress is caused both by the init ial rate of
production of superoxide and the rate of their conver-
sion into OH
•
radicals. The former can be induced by
hypoxic conditions such as occur at high altitude, and
one prediction, that is borne out [487, 530], is that PE
should therefore be more prevalent at h igh altitude.
Erythropoietin may be a marker for oxidative stress in
pre-eclampsia [531].
Regarding the second stage, predictions include that PE
should be m ore common in those suffering from
diseases of iron metabolism. Although such mothers
are of course less well apriori, this prediction is borne out
for a-thalassemia [532, 533] although not, interestingly,
for haemochromatosis [534]. We note in this context
that thalassaemia not only predisposes towards PE but is
known in general to cause hepcidin to decrease and
NGAL to increase [352, 353, 356, 53 5], with consequent
and inevitable iron dysregulation.
Another prediction is then that hepcidin should be
changed in pre-eclampsia. Although no serum measure-
ments have been reported to date, it is of extreme interest
that – while they took it to be an antimicrobial peptide
rather than an iron regulator – a recent study by Knox and
colleagues of placental gene expression in a mouse model
of PE showed that hepcidin expression
increased by a
greater factor than that of any other gene save one [536],
consistent with the view that major changes in the
regulation of iron liganding and metabolism underpin PE.
Finally, we note that NGAL is significantly implicated in
pregnancy, and was even named uterocalin in mice to
reflect its high expression in the u terus [361, 537-539]. A
very recent study [540] suggests that it may be a useful
second trimester biomarker for pre-eclampsia.
Diabetes
Type 2 diabetes and insulin resistance are known
complications of pregnancy (e.g. [541-54 5]), and also
predispose towards PE. In a similar vein, various types of
pregnancy-related intrauterine growth restriction predis-
pose towards diabetes in later l ife [546, 547], pointing
up the progre ssive nature of these syndromes. Metabolic
biomarkers for the one can thus be predictive of the
other [548], consistent with a common cause. Certainly
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ROSs are known to play a substantive role in both
insulin resistance [549- 556] and in a variety of diabetic
sequelae [95, 55 7-559], and mitochondrial dysfunction
may be an early step in this [560]. Some anti-diabetic
drugs, such as the 'glitazones' that are considered to act
on Peroxisome Proliferator Activated Receptor (PPAR)g,
may also act by decreasing ROS production (e.g.
[561-565]), and are even active aganst cerebral isc haemia
and stroke [566-569]. As with most if not all of the other
diseases we review here, studies of pro-inflammatory
markers (such as TNF-a, IL-1 and C-reactive protein
[570]) during the development of diabetes show its
aetiology to be inflammatory in nature [553, 571-590].
Iron 'excess' is also a known feature of gestational
diabetes [591-593], and is a clear risk factor for the
disease even in 'normal' populations [594-603], and
indeed diabetes is a classical cons equence of iron
overloading as seen in hereditary haemochromatosis
[604]. Serum ferritin and body iron stores are strongly
associated with diabetes [603, 605-609], including
prospectively [610], while changes in visfatin are also
intimately involved in changes of iron metabolism (with
pro-hepcidin being elevated) [611]. Most importantly,
lipocalin 2 (siderocalin/NGAL) is strongly associated
with the development of d iabetes [612, 613]. Lowering
iron improves insulin sensitivity [598, 614], and
metallothionein is also protective [615-619]. There
seems little doubt that iron status is a major determinant
of the development of type 2 diabetes [620].
Non-transferrin-bound iron is also considerably elevated
in type 2 diabetes [621], and this too is exacerbated by
vitamin C. Iron metabolism is substantially deranged in
type 2 diabetes and the metabolism of glucose (a
reducing sugar) interacts significantly with iron metabo-
lism [598 ]. Iron is also strongly i mplicated in non-
alcoholic steatohepatitis, considered an early marker of
insulin r esistance [622-624]. Well-known diabetic com-
plications include retinopathies, and it is noteworthy
that elevated levels of ferritin can lead to cataract
formation [625, 626].
The metabolic syndrome
Although some of its origins may be pre-natal [547],
many of the features of these diseases are also seen in the
(so-called) Metabolic Syndrome [627 -631]. Thus, serum
ferritin is also relate d to insulin resistance [606, 632,
633] and iron levels are raised [624, 634, 635]. Of course
diabetes and the Metabolic Syndrome are also closely
coupled, so it is reasonable that features observed in the
one may be observed during the development of the
other. The metabolic syndrome is also an independent
indicator for chronic kidney disease [636] and may be
related to liver steatosis [637]. Metabolic disorders of
this type t oo are closely intertwined with inflammation
[575, 581, 587, 638], that is of course stimulated by
ROSs whose generation i s increased by high-fat diets
[639]. Thus, our role here is to point up the existence of a
considerable body of more-than-circumstantial evidence
that here too the progressive and damaging nature of
these diseases may be caused, in part, by inappropriately
chelated iron.
Obesity
"As previously pointed out by Booth et al. [640], 100%
of the i ncrease in the prevalence of Type 2 diabetes and
obesity in the United States during the latter half of the
20th century must be attributed to a chan ging environ-
ment interacting w ith genes, because 0% of the human
genome has changed during this time period." [629]
It is well known that there has been a staggering increase in
the prevalence of obesity, diabetes, and especially type 2
diabetes, in the last 50 years or so, and that this increase is
expected to continue (e.g. [641-643] and http://www.who.
int/diabetes/). Equally, it is now well known that obesity,
metabolic syndrome, diabetes and cardiovascular diseases
are all more or less related to each other [643], and the
question arises here as to whether dysfunctional iron
metabolism might be a feature of each of them. In the
case of obesity per se, however, we see no major evidence as
yet for a causative role of deranged iron metabolism or
chelation in causing obesity. Indeed, while they are related
[644], what little evidence there is [645, 646] suggests that
the converse may be true, i.e. that changes in iron
metabolism might be consequent upon obesity (possibly
via peroxide generation [639]). Importantly, considerable
evidence suggests that obesity and inflammation are
significantly related [163, 486, 575, 581, 642, 647-664],
not least because adipocytes produce and release various
adipokines including pro-inflammatory cytokines such as
IL-6 and TNF-a [575, 649, 650, 665-671]. It is likely that it is
the
combination of overfe eding-induced obesity and
inflammation (partly induced by the obesity itself [672])
that leads to diabetes [673]. Certainly there is evidence for
increased ROS production in obese mice, possibly mediated
in part via the fatty acid-induced activation of NAPH oxidase
[674], while obesity is linked [675, 676] to urinary levels of
8-epi-PGF
2a
, a well established marker of oxidative stress
(qv). Fig 5 summarises the above in a manner that stresses
the roles of iron, overfeeding and inflammation in the
genesis of these processes, and notes that interference in
several of these steps is likely to be required to limit their
progression to best advantage.
Hypertension
As well its significance in pre-eclampsia (see above),
hypertension is a well known risk f actor for many
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cardiovascular and related disease (e.g. [677]), and there
is considerable evidence that its underlying cause is
inflammatory in nature [678-686], is related to the
metabolic syndrome and obesity (e.g. [648, 687-691]),
and may be mediated mainly via ROSs [692]. There is
evidence that some of its sequelae may be mediated via
iron [693, 694].
Cardiovascular diseases
It is well known that elevated iron stores can predispose
to coronary artery disease and thence myocardial
infarction. The 'iron hypothesis' of the benefits of some
iron depletion due to menstruation was devised to
account for the lowering of heart-disease risk in young
women (that disappears in those post-menopause) and
was proposed by Jerome Sullivan in 1981 [695-698]
(and see also [699, 700]). (In this s ense, the lack of
menstruation during pregnancy would predispose to a
comparative abundance of iron, as is indeed found – see
above.) It is of particular interest that the well-known
adverse vascular effects of homocysteine (in inhibiting
flow-mediated dilatation) are in fact iron-dependent
[701-703], and that reducing homocysteine (e.g. by
folate supplementation) in the absence of lowering iron
has shown no cli nical b enefi t to date [704], thereby
suggestion iron mediation. By contrast, iron stores
represent an established risk factor for cardiovascular
disease [705].
Of course many factors such as lipid levels, stress,
smoking and so are well-known risk factors for cardio-
vascular, coronary a rtery disease and related diseases.
Indeed kidney disease is well established as a risk factor
forcardiovasculardisease[706-708](andindeedstroke
[709]), all consistent with their having in part a common
cause – we believe inflammation). Our purpose here,
within the spirit of this review, is to indicate the evidence
for the involvement o f inappropriately chelated iron in
cardiovascular diseases too. There is no doubt that the
iron-mediated causal chain of ischaemia Æ (su)peroxide
Æ OH
•
radical formation occurs during the develop-
ment of heart disease, especially during reperfusion
injury [710-713], and suitable iron chelators inhibit this
[714, 715] (see also [716, 717], and f or thalassaemia
[718]). Iron is also involved in the protection that can be
produced by ischaemic preconditioning [719, 720].
Erythropoietin, a hormone with multiple effects that
may involve iron metabolism, is also protective [721,
722].
Heart failure
The sequelae of heart failure are complex, and involve a
chronic and continuing worsening of a variety of
physiological properties. ROSs are certainly involved
here, since allopurinol (a potent inhibitor of xanthine
oxidase) improves prognosis considerably [723], and
uric acid is a well known biomarker for heart failure (see
e.g. [724, 725]). Biopyrrins, degradation products of
bilirubin and thus markers of oxidative stress are also
considerably increased [726]. Anaemia is a common
occurrence (and risk factor) in heart failure [727-729],
again implying a role for dysregulated iron metabolism
and a need to understand the exact speciation of iron in
chronic anaemias linked to inflammatory diseases [730].
It is next on the formation of atherosclerotic plaques that
our attention is here focussed.
Atherosclerosis
Atherosclerosis is a progressive inflammatory disease
[731-762] characterized by the accumulation of both
oxidised lipids and various fibrous elements in arteries,
often as plaques [763, 764]. Iron and oxidised lipids a re
both found in atherosclerotic lesions [141 , 76 5-777],
and iron depletion by dietary or other means delays this
[778-782]. There is a correlation between iron status and
atherosclerosis [766, 776, 783-794], evidently c aused in
part by the known ability of poorly liganded i ron to
effect lipid [76 5, 784] and protein peroxidation, and by
the effects of primed neutrophils [795] and transferrin
[758]. In this context, exogenous ferric iron is deleterious
to endothelial function [796], while ir on chelati on
improves it [797-800]. However, phlebotomy provided
no clinical benefit here [801]. Note that iron levels in
plaques correlate with the amount of oxidised proteins
therein [771], and that in one study [767], the EPR-
detectable iron (essentially Fe(III)) in atherosclerotic
tissue was
seventeen times greater than that in the
equivalent healthy ti ssue; this is not a small effect . (Iron,
Figure 5
Role of inflammation caused by hydroxyl radical
formation in the interactive development of obesity,
the metabolic syndrome and diabetes.Interventionat
multiple steps is likely to be most beneficial i n alleviating this
kind of progression.
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as part of the general ROS cascade, has also been
implicated in gallstone formation, where melatonin has
proved protective [802, 803].)
Statins, typically developed on the basis of their ability
to inhibit the enzyme HMG-CoA redutase and thus
decrease serum cholesterol, are well established to have
benefits in terms of decreasing the adverse events of
various types of cardiovascular disease [804], albeit that
in m any populations (e .g. [805-807]) cholesterol alone
is a poor predictor of cardiovascular disease, especially in
the normal range. However, a known target of statins
different from HMGCoA reductase is the b
2
-integrin
leukocyte function antigen-1 (LFA-1) [80 8, 809] and in
this context, it is important to note that the clinical
benefits of the statins are certainly
not due solely to their
cholesterol-lowe ring ability via the inhibition of HMG-
CoA reductase (see e.g. [163, 281, 650, 807, 808,
810-840]), and dif ferent statins can cause a variet y of
distinct expression profiles [841] that are inconsistent
with a unitary mode of action. The apparent paradox
[842] that lipid-lowering statins do indeed exhibit
epidemiological disease-lowering benefit , while having
little effect on plaques, is arg uably wel l explained,
especially within the context of the present review, via
their additional anti-inflammatory e ffects [817, 819,
843-863, 163, 807, 823-825, 830, 836, 837, 864-892],
acting upst ream of the nuclear trans cripti on factor NF-B
(and see later). It is also extremely relevant, for instance,
that some statins have metal chelating properties [893].
It has been pointed out that many measures of iron stress
are inappropriate, since it is only the redox-active form
of iron that is likely i nvolved in oxidative stress. Serum
ferritin is considered by some to be the most reliable
marker of iron status in general [894], although it i s not
well correlated with iron dist ribution in the heart [895],
for instance. What is clear, however, from the above is
that deranged iron metabolism is intimately and causally
involved in the formation of atherosclerotic lesions, and
that appropriate iron chelation can help both to prevent
and to reverse this.
Iron status is also closely involved in other chronic vascular
diseases, and in the behaviour of wounds [896-899].
Stroke
Stroke is caused by ischaemia, leading to inflammation
[900] and to the formation of ROS and other damaging
free radicals [901] in the brain (which is high in metal
ions [902]), and is exacerbated by existing inflammation –
see e.g. [903, 904]. Thus, another prediction is that iron
excess should also aggravate the sequelae of stroke, and
that appropriate chelation or free radical trapping agents
should mitigate these effects. These predictions are indeed
borne out [138, 905-914]. It is also of considerable interest
that plasma NGAL levels are increased in stroke [406]; it is
noteworthy that this can be seen in plasma despite the
localised origin of the disease.
A v arie ty of ot her studies have sho wn the beneficial
treatments in stroke models of anti-inflamm atory and
antioxidant treatment, i .e. treatments that lower the
amountofROSs(e.g.[915-922]),aswellasof
preconditioning [923]. Given its r ole in iron metabo-
lism, it is of considerable interest that erythropoietin
also seems to be very effective in protecting against brain
ischaemia/reperfusion injury and stroke [924-939], by a
mechanism independent of erythropoiesis [940-942],
and one that appears to involve anti-inflammatory
activity [943].
Alzheimer's, Parkinson's and other major
neurodegenerative diseases
Oxidative stress and inflammation are early events of
neurodegenerative diseases [920, 944-957] such as
Alzheimer's dis ease (e.g. [958-973]), where plaque
formation precedes neurodegeneration [974]. Iron (and
in some cases copper) is also
strongly implicated in a
variety of neurodegenerative diseases [944, 981, 945,
958, 982-985, 962, 986-989, 950, 990-1021, 917,
1022-1034, 278, 1035-1055, 43, 1056-1059, 285,
1060, 972, 1061-1065, 141, 975, 1066-1087 ].
Indeed Thompson and colleagues comment [136] that
"The underlying pathogenic event in oxidative stress is
cellular iron mismanagement" and stress that "Multiple
lines of evidence implicate redox-active transition metals,
such as iron and copper, as mediators of oxidative stress
and ROS production in neurodegenerative diseases".
There is also ample evidence for its presence in the
plaques characteristic of Alzheimer's disease [ 1004, 1013,
1027, 1088], just as in those of atherosclerosis (see
above). Note too that iron can catalyse the oxidation of
dopamine to a quinine form that can bind covalently to
and then aggregate proteins [1089]. Kostof f [ 1090] has
used a very interesting literature-based discovery
approach to highlight the role of oxidative stress i n the
development of Parkinson's disease.
Other papers highlight the role of iron in multiple
sclerosis [899, 991, 1091-1098] and in prion diseases
[967, 1099, 1100]. However, a particularly cle ar example
of iron-mediated neurodegeneration is given by the
sequelae consequent upon lesions in a protein known as
frataxin involved in the disease Friedreich's ataxia (FA).
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Friedreich's ataxia
A number of repiratory chain components contain non-
heme iron, and the question arises as to how they
acquire it [1101]. Frataxin is a mitochondrial iron
chaperone protein [1102 -1109], involved in the safe
insertion of Fe(II) during the production of Fe-S centres
in the mitochondrial respiratory chain [1110]. As are
some other aspects of iron metabolism [1111], it is
highly conserved in eukaryotes from yeast to humans
[1112, 1113], a fact that made the unravelling of its
function considerably easier [1114-1123]. Friedreich's
ataxia (FA) is a neurodegenerative disorder that arises
from a genetic deficit of frataxin activity, whether by a
missense mutation or, much more commonly, via the
addition of GAA trinucleotide repeats [1107,
1124-1127]. As well as t he neurodegeneration and
measurable iron deposition, clinical symptoms include
cardiac hypertrophy [1128] and ( pre-)diabetes [1129 ],
consistent with the general thesis described here that all
are in part manifestations o f iron dysregulation, and in
which suit able chelation may be benef icial [1130, 1131]
(but cf. [1132]).
ROSs are undoubtedly involved in FA [1133, 1134],
specifically via Fenton chemistry [1135, 1136], since the
attenuation of H
2
O
2
production (but not of superoxide)
[1110] ameliorates the disease [1137]. The deficit in
frataxin causes both an increase in ROS (H
2
O
2
)
production via the mitochondrial electron transport
deficiency [1138] as well as a dysregulation in iron
metabolism, potentially a very damaging synergistic
combination (see later). Elements of its (in)activity
that are seen as paradoxical [1139] are in fact easily
explained when one recognises that i t is the combination
of free iron with H
2
O
2
that is especially damaging. The
neonatally lethal GRACILE syndrome is also caused by a
failure of iron chaperoning into mitochondrial complex
III due to mutations in the BCS1 L gene [1140, 1141].
Amyotrophic lateral sclerosis (ALS) or
Lou Gehrig's disease
ALS is another progressive inflammatory [1142] disease
in which motor neuron death causes irreversible wasting
of skeletal muscles. It has largely defied efforts to
uncover the genetic basis of any p redisposition [1143 ],
save for a very clear association with defects in a Cu/Zn
superoxide dismutase [33, 1144-1146] that can
obviously lead to an increase in the steady-state levels
of superoxide (and hence hydroxyl radical formation).
There i s also significant evidence for the involvement of
iron [1147, 1148]. Drug therapies have to date shown
rather limited benefits, and more in mouse models of
Cu/Zn SOD defi cie ncies than in humans , th ough i ron
chelation therapy does not seem to have figured heavily,
and it is recognised t hat combination therapies might
offer better prognoses [114 9].
Aging
Aging or senescence is defined as a decline in perfor-
mance and fitness with advancing age [1150]. Iron stores
tend to increase with age [1151-1155], partly due to
dietary reasons [1156] (and see [1157, 1158]) , as does
anaemia [1159, 1160]. So too does the expression of
NGAL/Lcn2/siderocalin, a process that can be reversed
by melatonin [1161]. Mainstream theories of aging [163,
165, 1162-1180] recognise t he relationship between
progressive inflammation, cellular damage and repair
and the higher-level manifestations of the aging process,
and ('the fre e radical theory of aging' [1163, 1181])
ROSs are of course strongly implicated as partial
contributors to the aging process (e.g. [31, 43, 980,
1163, 1 182-1206]). Needless to say, not least because of
the low stea dy-state net rate of generation of the various
ROSs [1207], few studies have managed to be very
specific mechanistically [1208], but it should be clear
that all ROSs are not created equal and we need here to
concentrate mainly on the 'nasty' parts of ROS metabo-
lism, and in particular on the hydroxyl radical as
generated via poorly liganded iron and on peroxynitrite,
and to have the greatest effects we need to inhibit both
their generation and their reactivity (see S ystems Biology
section, below). The iron content of cells also increases
as cells age normally [1209]. As many diseases increase
with age, probably via mechanisms h ighlighte d herein,
treating aging can thereby t reat disease [162], and it is
important to recognise that most 'diseases' are in fact
consequences of aging (despite the considerably greater
historical focus on the former).
Frailty
One issue of aging is not that just it happens but that it
can manifest in a series of essentially undesirable
physiological c hanges, referred to as frailty [1210], in
which ROSs have also been strongly implic ated. Indeed,
there are many parts o f physiol ogy and me tabolism that
lose functionality during aging (e.g. the cardiovascular
system [1211] and of course cognitive function [1212]),
and iron metabolism is known to change considerably as
humans age [980, 1213], with anaemia a typical
accompaniment of aging [1214]. The question then
arises as to how much of this deranged iron metabolism
is causal in accelerated aging, and this is not easy to state
at this time. However, lowering iron does i ncrease the
lifespan of Drosophila [1215] and yeast [1105]. At all
events, the purpose of this rather brief section is to point
out to researchers in aging, frailty and gerontology
generally the relevance of inadequately controlled iron
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metabolism as a major part of ROS-induced injuries that
may accelerate the aging process.
Longevity
Although aging and longe vity are not of course the same
thing, and longevity is not a 'disease', studies of aging are
often performed with the intention of improving our
understanding of longevity [1216], and cert ainly long-
evity is linked to age-related disease [1217]. However,
the longevity of many organisms can be varied by the
manipulation of any number of diseases or processes.
This said, caloric or dietary restriction is a well-known
contributor to longevity (indeed the only reliable one in
pretty well all s pecies [1218-1 223] – although possibly
not H. sapiens [1180]), and appears to act at the root of
the processes involved [1224]. Caloric r estriction appears
to be associated with a considerably lowered rate of
production of ROSs and accrual of ROS-induced damage
[1207, 1225-1228], and this is to be expecte d on general
grounds in that a restriction of substrate supply will
make the redox poise of mitochondria [1229] more
oxiding and thereby minimise the amount of 1- and 2-
electron reductions of O
2
to form peroxide and super-
oxide. It is therefore also of great interest that caloric
restriction also b enefits iron status [1230] and that it is
this improved iron status that in part promotes longevity
[1231]. Caloric restriction has also been shown t o effect
a differential stress res ponse between normal and
tumour cells [1232], although this study did not look
at relative iron status.
Antioxidants can also influence lifespan. Thus (rather
high doses of) melatonin extended the lifespan (and
stress resistance) of Drosop hila [1191, 1233-1235] w hile
that of Caenorhadbitis elegans could be extended by
mimics [1236] of SOD and catalase [1187], and by a
variety of antioxidant and other pharmacological agents
[1237].
As an example, let us consider C. elegans.Mutantswitha
decreased activity of the insulin-like growth factor
signalling pathway (e.g. daf2 mutants that have a greater
amount of the DAF16 FOXO-like transcription factor)
can live for nearly twice as long as wild types [1238,
1239] and produce more catalase, superoxide dismutase
(sod-3) [1240] and glutathione-S-transferase.
Overall, it is the potent combination of oxidative stress,
already leading to damaging peroxides and radicals, and
its catalysis and further reactions caused by inappropri-
ately chelated iron, that causes a 'double whammy'.
Indeed, iron, copper and H
2
O
2
have been referred to as
the 'toxic triad' [1032]. While there is comparatively little
that we can do about the production of superoxide and
peroxide, we can (by pharmacological or dietary means)
try and improve the speciation of iron ions.
Rheumatoid arthritis
One disease whose aetiology is well known to be bound
up with ROSs is rheumatoid art hritis (RA) [36,
1241-1246]. What is known of the r ole of iron
metabolism? G enerally an overall low iron status –
anaemia – is a char acteris tic of r heumatoid arthriti s
[1247-1251], whereas by contrast iron is elevated in the
synovial fluid of arthritic joints [12 52-1255]. This
suggests a significant derangement of iron m etabolism
in RA as well, and a mechanism [1256-1259] in which
elevated superoxide liberates free iron from ferritin in
synovial fluid (and elsewhere [1260]), thereby catalysing
further t he damaging production of hydroxyl radicals.
This autocatalytic process (Fig 6) is, even in principle,
especially destructive (and may account for species
differences in sensitivity to iron loading [1261]). Note
that erythrocytes when oxidized can also release free iron
[524]. Natural antioxidants such as vitamin E are also
lowered [1262]. There is some evidence that appropriate
iron chelators can ameliorate the symptoms of RA
[1263], though membrane-impermeant chelators such
as desferroxamine cannot [1264].
One interesting feature of RA is that in 75% of women it
is strongly ameliorated during pregnancy [1265-1267];
although the multifactorial nature of this observation
has made a mechanistic interpretation difficult, from
everything that we have seen so far it would be surprising
if changes in iron metabolism were not strongly
involved.
An interesting related feature is the 'restless legs
syndrome' [1268-1270], that is often associated with
Figure 6
CatalysisandautocatalysisintheHaber-Weissand
Fenton reactions leading to the production of the
hydroxyl radical, including the liberation by
superoxide of free iron from ferritin.
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iron deficiency and pregnancy. Serum transferrin recep-
tor seems to be a rather sensitive measure of this iron
deficiency [273, 1271, 1272]. There are relationships
with other syndromes that we discuss h ere, such as
cardiovascular disease [1273], but in the present review
it is of especial interest that a dysregulation of iron
metabolism appears to play a significant role [1274]
Lupus (Systemic Lupus E ryt hematosus )
Lupus, or Systemic Lupus Erythematosus (SLE) [1275,
1276] describes a syndrome, somewhat related to
arthritis and rheumatism, of broadly auto-immunologi-
cal or inflammatory origin, and with a large variety of
manifestations (e.g. [1 277-1285]), but characterised in
particular by fatigue [1286 ], often as a result of anaemia.
This of course points to a certain level of iron
dysregulation (of any number of ca uses), and there is
certain some evidence for t his [1274, 1287]. Thus, while
anaemia is a feature of the disease, serum ferritin may be
raised in SLE [1288], and some of the usual lipid markers
of oxidative stress (that can be a result of hydroxyl
radical production catalysed by poorly liganded iron) are
also present [1289].
There is also a very interesting linkage between SLE and
vitamin D m etabolism [1290], something that has also
come up in relation to the s tatins and atherosclerosis
([832, 1291], but cf. [1292]) , and indeed it there is
evidence that statins may be of benefit in the treatment
and even reversal of lupus [1293, 1294]. Indeed, from a
much more general point of view, there is precedent for
these kinds of linkages being used to uncover unknown
mediators in disease states that may be worth pursuing
(e.g. [6, 19, 20, 1295, 1296]).
Asthma
Asthma is a well-known inflammatory disease, and has
been linked with ROS gene ration [1297] catalysed by
iron [276, 1298-1300].
Inflammatory bowel diseases (IBD)
By definition, IBD such as Crohn's disease and ulcerative
colitis are inflammatory diseases, and while the inflam-
mation and ROS production are well established here,
their origins are somewhat uncertain [1301-1304]. They
are frequently accompanied by anaemia, implying a
derangement in iron absorption and/or metabolism
[1305, 1306], and very probably absorption [ 1307,
1308]. T he anaemia may be monitored by ferritin and
transferrin receptor levels, and its correction is possible
by iron supplementation plus erythropoietin
[1309-1315]. One may suppose that some of the issues
here relate to iron speciation, that is usually not
measured in these studies.
Age-related macular degeneration
Age-related macular degeneration (AMD) [1316] is now the
leading cause of blindness and visual disability in the elderly
in developed countries [1317-1320]. Many components of
atherosclerotic plaques have also been demonstrated in
drusen [1321], a characteristic of AMD and, as here, it is
reasonable to propose a common mechanism of pathogen-
esis between AMD and atherosclerosis. Retinal iron levels
increase with age [1322], iron is significantly implicated in
AMD [1323-1329], and iron chelation may help to reverse
the process [1330]. Dietary antioxidants are also protective
[1331]. The source of the iron appears to be excess
angiogenesis and leakage from blood vessels catalysed by
VEGF, and a PEGylated aptamer [1332-1334] against VEGF
(pegaptanib) or a monoclonal antibody (ranibizumab)
have shown significant promise in the treatment of macular
degeneration [1335-1340]. Plausibly a combination ther-
apy with one of these plus a suitable iron chelator might be
even more effective.
Psoriasis
Psoriasis i s an anflammatory disease in which the
production of free radicals and ROSs are strongly
implicated [1341-1343]. Here too there is clear evidence
for the involvement of a deranged iron metabolism
[1343-1345]. Early attempts at therapy with a series of
unusual iron chelators (that unfortunately had side
effects) [1346] do not seem to have been followed up.
Gout
Gout is another important inflammatory disease, char-
acterised by the accumulation of uric acid [1347]. There
is considerable evidence that this too is a disease of iron
overload, and that uric acid accumulation – as both an
antioxidant and an iron chelator [1348] – is in response
to the iron overload [1349, 1350] and with highly
beneficial remission of gouty symptoms occurring on
depletion of iron by phlebotomy [1351].
Alcoholic and other forms of liver disease
It is known that with chronic excess, either iron or alcohol
alone may individually injure the liver and other organs,
and that in combination, each exaggerates the adverse
effects of the other. Specifically, in alcoholic liver disease,
both iron and alcohol contribute to the production of
hepatic fibrosis [1352-1358]. Iron overload is well known to
lead to hepatotoxicity [1359-1362] and liver cancer [1363,
1364], and lowering or chelating it is protective [1365,
1366]. Hepcidin may be involved here [1367].
Chronic obstructive pulmonary disorder (COPD) and
related l ung diseases
Chronic obstructive pulmonary disease (COPD) is a
progressive and chronic disease which is characterised by
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an apparently inexorable decline in respiratory function,
exercise capacity, and health status. It is also charac-
terised by periods in which the symptoms are consider-
ably exacerbated [1368-1371]. Such an acute
exacerbation of COPD (AECOPD) is d efined [1372] as
"a sustained worsening of the patient's condition from
the stable state and beyond normal day to day variations,
that is acute in onset and necessitates a change in regular
medication in a patient with underlying COPD".
Smoking is a major source of free radicals (and indeed
metals [1373]), and is a major cause of COPD.
Consequently, there is considerable evidence for the
evidence for the involvement of i nflammation and ROSs
in both the 'stable' and 'exacerbated' stages [1374-1381].
Needless to say, there is also considerable evidence for
the significance of exposure to iron [1382] (as well as
exposure to other toxic metals [1383]) in the develop-
ment of COPD and other lung diseases [1384]. Haem
oxygenase also appears to be a significant culprit [280],
and lung (lavage) iron is increased [1385] while
transferrin levels can be considerably lower [1386].
Other l ung diseases in which ROS and iron have been
implicated include Adult Respiratory Distress Syndrome
[1387-1390] and cystic fibrosis [139 1].
Smoking
Tobacco smoke contains many unpleasant and carcino-
genic compounds, and that tobacco smoking is a leading
cause of carcinoma of the lung and indeed of other
organs has become well known since the pioneering
epidemiological studies of Doll, Peto and colleagues
(e.g. [1392-1395]). Our purpose here is to point out that
many of the particles associated with smoking (and also
ingested from other sources) are heavily laden with
micro-particulate iron, which, as a major catalyst of
hydroxyl radical production, undoubtedly is a sub-
stantial contributor as well (see e.g. [1373, 1384,
1396-1400]).
Cancer and oncology
In addition to the issues of smoking, the development of
cancer can certainly contain an inflammatory compo-
nent (e .g. [1401-1425]), and indeed the long-term use of
prophylactic anti-inflammatory aspirin lowers colon
cancer incidence by 40% (age-adjusted relative risk =
0.6) [1426 ] (though note that this may have other side-
effects [1427]). (The well-known association between
infectious agents such as H. pylori [1428-1430] and e.g.
bowel cancer is probably initiated by chronic inflamma-
tion.) Given that cells require iron, restricting its supply
can also limit the growth of cells, including tumour cells
[1431-1442]. Conversely the iron carrier NGAL is
overexpressed in tumours [410, 411, 1443], a process
mediated via NF-B [1444 ] (and see later). Furthe r, the
roles of iron, not least in t he mutagenic effects of metal-
catalysed Fenton chemistry, are also of significance in
promoting oncogenesis [1445-1461 ]. Iron chelators
[1438, 1462] are thus a doubly attractive component
of anti-cancer therapeutics. The mutagenic, carcinogenic
and disease-causing actions of asbestos and related fibres
may also be due in significant measure to the ability of
the Fe(n) that they contain to catalyse hydroxyl radical
production [1463-1475], while there seem to be com-
plex relations between the likelihood of apoptosis and
the differential concentrations of superoxide and H
2
O
2
[1476, 1477]. Overall, it is becoming increasingly widely
recognised that anti-inflammatory agents have a role to
play in the treatment of cancers; we woul d s uggest that
iron chelat ion may be a usefu l component of such
treatments.
Malaria
Just as do tumour cells, the malarial parasite Plasmodium
falciparum re quires considerable iron for growth, and
there is evidence that lowering the amount of available
iron provides a promising route to antimalarials (e.g.
[1478-1494], but cf. [1495]). Note in this context that
iron-catalysed radi cal forma tion is also significantly
involved in the antimalarial (i.e. cytotoxic) mode of
action of artemisinin [1494, 1496-15 04], and this
reaction is in fact inhibited by iron chelators [1505]
such that
a combined artemisinin-chelator therapy
would be contraindicated.
Antimicrobials
Lower down the evolutionary scale, and as presaged
earlier in the section on bacterial siderophores, microbes
require iron for growth, its presence may be limiting
even at the scale of global CO
2
fixation [1506-1509 ], its
excess can in some c ircumstances [ 1510] correlate with
infectivity or virulence (see above and e.g. [180, 193,
1493, 1511-1531]) , and its chelation in a form not
available to bacteria offers a route to at least a
bacteriostatic kind of antibiotic or to novel therapies
based on the lowering of iron available to microbes by
using hepcidin [1532] or NGAL [1533]. Iron chelators
are also inhibitory to trypanosomes [1534, 15 35], and
changes in iron metabolism are also associated with viral
infections [1536].
Sepsis leading to organ failure and death: severe
inflammatory response syndrome
It is well known t hat one consequence of bacterial
infection (sepsis) can be septic shock , that this can be
mimicked by the Gram-negative bacterial outer mem-
brane component LPS (lipopolysaccharide), and that in
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the worst cases this leads via multiple organ failure to
death. However, whatever LPS does it is quite indepen-
dent of the present of viable (i.e. growing or culturable –
see [1537, 1538]) bacteria as the same phe nomena
leading to multiple organ failure (MOF) are seen
without infection [1539, 1540]. Consequently, the
recognition of a series of symptoms contingent on this
initial i nflammatory response has led to the development
of the idea of a Systemic Inflammatory Response Syndrome
(SIRS) [1541-1551] that leads to the MOF, both via
apoptosis [1552] and necrosis [1553, 1554]. There is by
now little doubt that these phenomena too are associated
with the hyperproducti on of ROSs [1546, 1551,
1555-1570]. Circulating free iron is raised in sepsis and
related conditions [1400, 1571-1573]. Direct assays of
oxidant induced cell death indicate that most 'free' iron is
concentrated in lysosomes [1574-1577], that its decom-
partmentation is substantially involved [1570], and that its
chelation can thus prevent cell death [1578-1581].
Many circulating inflammatory factors have been identi-
fied as important in the development of septic shock,
including cytokines such as Tissue Necrosis Factor (TNF)
[1582], and cellular responses via the Toll-Like Receptor
are clearly involved in this process [1583, 1584]. However,
we would argue that since antibodies against TNF do not
inhibit the sequelae of septic shock such as multiple organ
failure, the truly damaging agents are caused elsewhere and
are likely to involve the iron-mediated production of
damaging hydroxyl radicals (see also [1563]).
In this regard, it is especially interesting that the
antioxidant melatonin is particularly effective in pre-
venting septic shock [1585-1587], and a variety of
suitable antioxidants have shown potential here [1573,
1588-1591], notably in combination with i ron chelators
[1592, 1593] (and see a lso [1594, 1595]). As with quite
a number of the indications given above, a further link
with Fe metabolism is seen in the protective effects of
erythropoietin [1596, 1597].
Pro- and anti-oxidants and their contributions
to cellular physiology
A very great many cellular metabolites are redox active
within the range of redox potentials realistically acces-
sible t o biology (including some molecules such as
proline [1598] that are not commonly considered to be
redox-active), and it is not our purpose here to list them
extensively. Not only their redox potential and status but
even their absolute amounts can have profound effects
on metabolism [1599]). Our chief point here is that it is
the intersection of iron metabolism and oxygen
reduc-
tion that needs to be the focus, with the 'iron'-catalysed
production of hydroxyl radical being the nexus, with the
standard redox potential of a redox couple per se being
less significant in absolute terms, and the redox potential
that a particular redox couple 'feels' being dependent in a
complex manner on a variety of thermodynamic and
kinetic factors [1229]. Thus, although ascorbate is
'reducing' and an 'antioxidant', its reaction with O
2
,
especially when catalysed by Fe(II), produces superoxide
and thence OH
•
radicals that may be pro-oxidant. It is
this kind of stepwise multi-electron-transfer phenom-
enon that explains the otherwise possibly puzzling
observation of the oxidant-induced reduction of respira-
tory chain components (see e.g. [1600, 1601]). Conse-
quently, it is extremely unwise to make pronouncements
on the role of 'ROSs' without being quite explicit about
which ones are meant.
Thus anything – even an antioxidant – that e.g. by reaction
with O
2
produces superoxide, peroxide and hydroxyl
radicals will turn out to be a pro-oxidant if the flux to
superoxide and in particular to hydroxyl radicals is
stimulated. Thermodynamically, the 1-electron reduction
by ascorbate of dioxygen is disfavoured, with the 2-electron
reduction to peroxide being the thermodynamically pre-
ferred route. However, such reactions are heavily restricted
kinetically in the absence of any catalysts [130]. It is an
unfortunate fact that the oxygen-mediated "autoxidation" of
ascorbate does in fact occur at considerable rates when it is
accelerated by the presence of iron or other transition metal
ions [130, 1602-1606]. In a similar vein, 'free' or inade-
quately liganded Fe(II) catalyses the production of hydroxyl
radicals from oxygen plus a variety of natural biomolecules,
including adrenaline (epinephrine) [1607], haemin [1608],
and even peptides such as the amyloid-b involved in the
development of Alzheimer's disease [1009, 1027]. Dietary
antioxidants (see below) can therefore act in complex and
synergistic ways depending on iron status [1609]. In this
regard, the idea of using elemental iron plus ascorbate in
food supplements [1610] does not seem a good one.
It should be noted that there are also occasions, e.g. in the
decomposition of refractory polymers such as lignin, where
such radical production is involved beneficially [1611].
Finally, a variety of molecules can trap hydroxyl radicals,
including hippurate [1612], melatonin [1233, 1585,
1586, 1613-1631] and salicylate [1632].
Antioxidants as therapeutic agents?
Should we be including iron chelators in
such clinical trials?
Given the wide recognition of the importance of ROSs in
a variety of diseases as describe d above, many investi-
gators have considered the use of known antioxidants
such as vitamins C (ascorbate) and E (a-tocopherol) in
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preventative therapy. Although there have been some
successes (e.g. [1633]), the results have generally b een
decidedly mixed, with little clinical benefit (or even
actual disbenefit) following from their administration
[692, 1588, 1634-1639], e .g. f or ALS [1640], athero-
sclerosis [106, 764], cardiovascular disease [1641 -1645],
neuroprotection [1646], macular degeneration [1647],
pre-eclampsia [1648-1652], critical care medicine
[1653], aging [1165, 1168, 1654, 1655], lung disease
[1656], elective surgery involving ischaemia-reperfusion
[1657], all-cause mortality [1637, 1658], etc. One
interpretation for these disappointing results, that is
consistent with the general theme of t his r eview, involves
the recognition that a variety of
antioxidants can in fact
act as
pro-oxidants and thus actually promote the
production of OH
•
radicals in the presence of inappro-
priately or inadequately liganded Fe(II) [130, 528, 1602,
1604, 1659, 1660]. (One might also comment that the
intracellular location of the
antioxidants may be an
issue, and that the view that targeting them to
mitochondria may well have considerable merit
[1661-1663].) Thus any predictions about the utility or
otherwise of
antioxidants need t o take into account the
amount of 'free' iron present. In partic ular , we would
suggest that future trials of this type might beneficially
include appropriate iron chelators, whether alone or
with
antioxidants.
Liganding and reactivity of Fe(n)
Given the damage that iron-mediated OH
•
radical can
create, the question arises as to whether appropriate
chelators can inhibit this by inhibiting the production of
OH
•
, and while the answer is 'yes' the interpretation of
the relevant experiments is not always as clear cut as o ne
would wish [43]. This is because the OH
•
radical is so
reactive that its p roduction is normally assessed by
addition of the putative chelator and observation of its
effect on the rate of reaction of a target molecule such as
salicylate with the OH
•
gen erated. The abili ty of a
chelator to inhibit such a reaction can then occur not
only via a reduction in the rate of OH
•
production but by
trapping the O H
•
itself,aswellasbyothermechanisms
[1664]. This said, there is little doubt that iron chelators
can be highly pro tective, and it is man y ways very
surprising that their use is not more widespread.
We begin by noting that the reactivity of iron does vary
greatly depending upon its liganding environment [71].
Cheng et al.state[72]"Oxygenligands prefer Fe(III); thus, the
reduction potential of the iron is decreased. Conversely,
nitrogen and sulfur liga nds stabilize Fe(II); thus, the
reduction potential of the iron is increased. Therefore,
chelators with oxygen ligands, such as citrate, promote the
oxidation of Fe(II) to Fe(III), while chelators that contain
nitrogen ligands, such as phenanthroline, inhibit the
oxidation of Fe(II). Many chelators, such as EDTA and
Desferal (DFO), will bind both Fe(II) and Fe- (III); however,
the stability constants are much greater for the Fe(III)-
chelator complexes. Therefore, these chelators will bind Fe
(II) and subsequently promote the oxidation of the Fe(II) to
Fe(III) with the concomitant reduction of molecular oxygen
to partially reduced oxygen species. Since the maximal
coordinationnumber of iron is six,the hexadentate chelators
can provide more consistently inert complexes due to their
ability to completely saturate the coordination sphere of the
iron atom and, consequently, deactivate the "free iron"
completely. For example, DFO is a very effective antioxidant
in clinical application because of its potential to markedly
decrease the redox activity of iron [137]." However, it is not
easy to make hexadentate ligands orally active [1665].
Iron typically can coordinate 6 ligands in an octahedral
arrangement. Preferential chelation of the Fe(II) or the Fe
(III) form necessarily changes its redox potential as a
result of Le Chatelier's principle, and from Marcus theory
[1666-1669] the rate of outer-sphere electron transfer
reactions is typically related to differences in the free
energy change, i.e . the differences in redox potentials of
the interacting partners. In addition, it widely recognised
that [137] "The tight binding of low molecular {weight}
chelators vi a coordinating ligands such as O, N, S to iron
blocks the iron's ability to catalyze redox reactions. Since
the maximal coordination number of iron is six, it is
often argued that the hexadentate chelators can provide
more consistently inert complexes due to their ability to
completely saturate the coordination sphere of the F e
atom. Consequently, a chelator molecule that binds to all
six sites of the Fe ion completely deactivates the " free
iron". Such chelators are termed "hexidentate" {sic}, of
which desferrioxamine is an example. There are many Fe
chelators that inhibit the reactions of Fe , oxygen, and their
metabolites. For example, desferrioxamine ... (DFO)
markedly decreases the redox activity of Fe(III) and i s a
very effective antioxidant through i ts ability to bind Fe."
By cont rast, bidentate or tridentate chelators that bind to
only 2 or 3 of the available iron chelation sites,
especially when they bind to both Fe(II) and Fe(III),
can i n fact catalyse redox cycling and thereby promote
free radical generation [1437, 1665, 1670, 1671]. Thus,
the most potent iron chelators will normally be
hexadentate (but may consequently strip iron from
iron-containing enzyme and thereby have deleterious
side effects). Bi- or tri-dentate ligands should therefore
be at saturating concentrations for maximum effect.
Generally, the harder ligands that favour Fe(III) involve O
whereas softer ligands that bind Fe(II) involve N and S. The
type of ligand also influences the absorption spectrum of
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the ferric form of the chelator, such that conclusions can be
drawn about the types of group involved in the complex.
These charge transfer bands that appear on ligand binding
are at around 340 nm for carboxylates, around 425 nm for
trishydroxamates, 470 nm for bis-hydroxamates, 515 nm
for monohydroxamates, around 480 nm for tris-catecho-
lates, 560 nm for bis-catecholates and 680 nm for mono-
catecholates [173]. In addition, for tris-bidentate complexes
the complex can, on an octahedral arrangement, have two
different configurations, a left-handed propeller, termed
the Λ-configuration, and a righthanded propeller, the
Δ-configuration [173].
Iron chelators – thoseapprovedandusedclinically
A number of reviews (e.g. [1437, 1438, 1672-1678])
cover aspects of iron chelators that have had or may have
utility clinically.
Whitnall and Richardson [1062] list a number of useful
features of an experimentally (and clinically) useful iron
chelator. Thus, "A compound suitable for the treatment
of neurodegenerative disease should possess a number
of qualities, namely (1) strong affinity for FeIII, (2) low
molecular weight, (3) lipophilicity high enough to
accommodate permeation of cell membranes and the
BBB, (4) oral a ctivity, and (5) minimal toxicity [1062].
Also, partly because there are few trivalent ions other
than Fe(III) that the body actually needs, the major
synthetic focus has been on the design of FeIII-selective
chelators which feature " hard" oxygen donor atoms.
Additionally, under aerobic conditions, high-affinity
FeIII chelators will tend to chelate FeII to facilitate
autoxidation, such that high-affinity FeIII-selective com-
pounds will beneficially bind both FeIII and FeII u nder
most physiological conditions" [1062]. (Note that
liophilicity per se may not be relevant, as drugs require
carriers to cross membranes [18], and promiscuity and
off-target effects increase with lipophilicity [1679].)
Desferrioxamines are nonpeptide hydroxamate sidero-
phores compose d of alternating dicarboxylic acid and
diamine u nits. linked by amide bonds. They are
produced by many Streptomyces species [1680]. Desfer-
rioxamine B is a linear (acyclic) substance produced
(industrially) by the actinobacterium Streptomy ces pilosus
[1681], and is widely used as an iron chelator for the
prevention and treatment of the effects of iron overload.
It is commercially available as desferal (desferrioxamine
methane sulphonate), also known as deferoxamine in
the USA. It has been very effective in the treatment of a
number of diseases, leading to the view that such
molecules should have considerable therapeutic poten-
tial. A significant disadvantage of DFO is that it does not
seem to cross the intestine intact (despite the rather
catholic substrate specificity of intestinal peptide trans-
porters [1682-1685]) and must therefore be given
intravenously or subcutaneously. By contrast, another
chelator known as Deferriprone or L1 does appear to
cross cell membranes, but it is only bidentate.
Those with app roval for clinical use are few in number
and we deal with them first. Table 1 compares them with
the 'ideal' properties of a clinically useful iron chelator,
while Fig 7 gives the structure of the three most
Table 1: Comparison of the main av ailable iron c helat ors to an ide al chelation drug (modified from [2469])
"Ideal chelator" Deferoxamine Deferiprone Deferasirox
Route of administration Oral Parenteral, usually
subcutaneous or
intravenous
Oral Oral
Plasma half-life Long enough to give
constant protection from
labile plasma iron
Short (minutes); requires
constant delivery
Moderate (< 2 hours).
Requires at least 3-times-
per-day dosing
Long, 8– 16 hours; remains
in plasma at 24 h
Therapeutic index High High at moderate doses in
iron-overloaded subjects
Idiosyncratic side effects are
most important
Probably high in iron
overloaded subjects*
Molar iron chelating
efficiency; charge of i ron (III)
complex
High, uncharged High (hexadentate); charged Low (bidentate); uncharged Moderate (tridentate);
uncharged
Important side effects None or only in
iron-depleted s ubjects
Auditory and retinal
toxicity; effect s on bones
and growth; potential lung
toxicity, all at high doses;
local skin reactions at
infusion sites
Rare but severe
agranulocytosis; mild
neutropenia; common
abdominal discomfort;
erosive arthritis
Abdominal discomfort;
rash or m ild diarrhoea
upon initiation of therapy;
mild increased creatinine
level
Ability to chelate
intracellular cardiac and
other tissue iron in humans
High Probably lower than
deferiprone and deferasirox
(it is not clear why)
High in clinical and in in vitro
studies
Insufficient clinical data
available; promising in
laboratory studies
*Nephrotoxicity that has been observed i n non-iron-loaded animals has been minimal in iron-overloaded hum ans, but effectiveness is demonstrated
only at higher end of tested doses, a s discussed in [1693].
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common, viz. desferal (deferoxamine), ferriprox (L1 or
deferiprone) and exjade (ICL670 or deferasirox). (Dex-
razoxane, a hexadentate chelator, is also marketed
[1686].)
Desferal (deferoxamine) is the most used chelator for
historical reasons. It is hexadentate but is not orally
bioavailable. Ferriprox (deferiprone) is a bidentate
ligand (1,2-dimethyl, 3-hydroxypyridin-4-one). It is
orally bioavail able although comparatively high doses
are required, and it postdates desferal. "Deferiprone has
high affinity for iron and interacts with almost all the
iron pools at the molecular, cellular, tissue and organ
levels. Doses of 50–120 mg/kg/day appear to b e effective
in bringing patients to negative iron balance" [1687]. It
can have s omewhat better properties than desferal
[1688]. Finally, Exjade (ICL670) (deferasirox)
[1689-1702] is the most recent chelator approved for
clinical use, and is tridentate. It is orally active, and there
is a large bibliography at http://www.exjade.com/utils/
bibliography.jsp?disclaim er=Y. The recommen ded initial
daily dose of Exjade is 20 mg/kg body weight.
It is clear from Table 1 that in the time evolution from
deferoxamine through defe riprone to deferasirox there
has been a noti ceable improvement in the general
properties of iron chelators, although there are few
published data on the quantitative s tructure-activity
relationships of candidate molecules that might allow
one to design future ones rationally. What is certainly
clear is that there is a trade-off in properties, and that
appropriate chelators will keep iron levels intermediate,
i.e. not too low and not too high (a 'Goldilocks' strategy,
if you will), and that hexadentate molecules may
correspondingly be too tightly binding and strip iron
from important molecules that need it. What is
particularly important, as well as a good plasma half-
life, is the ability to cross cell membranes, as this is
necessary both for oral administration and for ensuring
that the chelator in question actually accesses the
intracellular 'free' iron pools of interest. Which carriers
are used for this in humans in vivo is presently uncertain
[18, 1703].
Drugs that have been approved forclinicaluseforother
purposes, but that also happen to be iron chelators
The high investment of time, money and int ellectual
activity ne cessary to get a drug approved clinically has
led to a number of strategies to exploit those that already
have been approved and are thus considered 'safe'. One
such strategy is the combination therapy of approved
drugs that c an yet serve for novel indications (e.g.
[1704-1708]). Another strategy is to look for antioxidant
or iron-binding chemical motifs in drugs that have
already been approved for other purposes [1709] (or to
measure such properties directly).
Clioquinol (CQ) [1062, 1674, 1710, 1711] (Fig 7) is one
existing (anti-parasitic) drug that has been proposed for
use as an iron chelator, as it contains the known iron-
chelating 8-hydroxyquinoline moiety. It h as indeed
enjoyed some success in this role. However, clioquinol
toxicity has been reported if it is used over a n extended
period [1712] and this may be due to the formation of a
Zn-clioquinol chelate [1713].
A particular attraction of such existing drugs is that they
are likely to have favourable pharmacokinetics and
pharmacodynamics, and in particular are likely to be
cell-permeable. Note that despite a widespread assump-
tion that lipophilicity or log P is s ufficient to account for
drug distribution this is not in fact the case, as there are
hundreds of natural transporters that drugs can use (e.g.
[18, 1714]). For instance, th e iron- chelating 8-hydroxy
quinoline motif contained in molecules such as clioqui-
nol is also pr esent in the tryptophan catabolite
xanthurenic acid (Fig 7), and it is likely that transmem-
brane transport of the synthetic drug molecule occurs via
natural carriers whose 'normal' role is to transport
endogenous but structurally related molecules [18,
1703].
Iron chelators that have been studied but not yet
approved
Given the importance of the field, many academic
investigat ors have sough t to develop their own iron
chelators th at might exhibit the desirable properties
listed above. One class of molecule includes
Figure 7
Some iron chelators that are in clinical use (left hand
side) or that have been proposed.
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isonicotinylhydrazones. Thus, pyridoxal isonicotinyl
hydrazone (PIH) [1672, 1715-1720] is a promising
molecule (also proposed in anti-cancer therapy),
although it is hydrolysed both in v ivo and in vitro
[1721]. Other analogues include salicylaldehyde (SIH)
[1722] and 2-hydroxy-1-napthylaldehyde (NIH) isoni-
cotinyl hydrazones. PIH was disclosed before being
patented, and is thus seen as having no pharmaceutical
(company) interest. Various other derivatives are there-
fore being considered [1035, 1462], including pyrazi-
nylketone isonicotinoyl hydrazones [1723].
A variety of 8-hydroxyquinolines (8HQs) [1724] have
been considered, although as with other bidentate and
tridentate ligands that cannot necessarily ef fect complete
liganding of iron there is always a danger that
inadequate concentrations might be pro-oxidant (e.g.
[1725, 1726]). One mole cule, VK-28, combines various
pertinent moieties and has shown some promise in the
treatment of neurological disorders [1727-1730]. This
strategy of combining drug elements that can hit
multiple targets ('polypharmacology' [807,
1731-1734]) has m uch to commend i t, including on
theoretical grounds, and we discuss these in the section
on systems biology below. Another 8HQ that has el icited
interest is O-trensox [1431, 1735-1742].
Other ligands or motifs that might be considered include
di-2-pyridylketone-4,4,-dimethyl-3-thiosemicarbazone
(Dp44mT), t hat has been shown to be effective against
tumours [1743], 2,2'-dipyridyl, 1,10-phenanthroline
[1744, 1745], 2- benzoylpyridine thiosemicarbazones
[1746] and thiohydrazones [1747]. HBED (Fig 7) (N,
N'-bis-(2-hydroxybenzyl)ethylenediamine-N,N'-diacetic
acid) forms a 1:1 complex with Fe(III) but is probably
only tetradentate [1748]. It seems not to be very orally
active [1749] but may be m ore effective than is DFO
[1750-1752]. Poly-hydroxylated 1,4-naphthoquinones
occur as sea urchin pigments and have shown protective
effects [1753].
Continuing the theme of polypharmacol ogy, R-(a)-
lipoic acid [1754-1757] is also an antioxidant, that
may in addition act by stimulating other anti-oxidant
pathways [1758]. Finally, one interesting area is that of
prochelators (e.g. [1759]) in which the oxidant itself
triggers the formation of a chelator able to inhibit the
Fenton reaction.
Utility of iron chelators in disease amelioration
Therapeutic uses of iron chelators have been widely and
usefully reviewed (e.g. [1437 , 1489, 1676, 1760-1767]).
Many problems remain, such as bioavailability, mis-
dosing [1768] (t oo little iron as well as too much of it
can be bad), toxicity, selectivity and so on, and their
design is consequently highly non-trivial [1665, 1670].
Nevertheless, iron chelators have demonstrated thera-
peutic benef its in Alzheimer's [1674, 1710, 1769-1771],
Parkinson's [1037, 1729, 1772], cold-induced brain
injury [1773, 1774], coronary disease [714, 797], renal
diseases [1775], various kinds of infection [1763] and of
course in iron overload diseases [1762, 1767].
As mentioned above, one i nteresting strategy is to devise
chelators that are only activated by oxidative stress
[1760, 1776-1779]. Another is to seek to combine
different kinds of functionality in the same molecule.
To this end, Youdim and colleagues in particular have
developed a series of multifunctional 8-hydroxyquino-
line [1740] derivatives that are effective bidentate iron
chelators and that seem to sh ow con siderable promise in
the treatment of a variety of neurodegenerative diseases
[1037, 1727-1729, 1780-1784] (see also US Patent
20060234927). In this case the antioxidative mechanism
is clearly via chelation since such (8-hydroxyquinoline)
molecules are poor scavengers of radicals direc tly [1785],
a fact that a lso makes them useful scientific tools. As
bidentate ligands they cross both cell membranes and
the BBB fairly easily (though lipophilicity per se seems
not to be important for the biological activity of 8-
hydroxyquinoline chelators [1737, 1739]) . Importantly,
the comparatively weak bidentate binders seem not to
have major long-term eff ects if used carefully [1 483,
1762, 1786, 1787]
Interaction of xenobiotics with iron metabolism
As Cherny and colleague s point out [1710], there are
many US Pharmacopaeia-registered drugs that, while not
being termed chelators, do in fact have both chelating
properties and favourable toxicity profiles. Thus we need
to recognise potentially both positive and negative
interactions between drugs in general and iron metabo-
lism. Any drug that can bind iron can also catalyse the
formation of free radicals. Thus, gentamicin can form a
gentamicin-iron complex that can lead to toxic symp-
toms such as hearing loss; this is reversed by iron
chelators [1788, 1 789]. E xisting d rugs other than iron
chelators may also have effects on iron metabolism
[1790], and iron can catalyse their oxidation [1791]. It is
not, of course, news that drugs have multiple effects. In
this context, we reiterate t hat some statins, for instance,
have chelating properties [893].
Other toxicants might also mediate their damaging
effects through iron-catalysed radical formation [1792,
1793]. This in addition to the well-known iron-catalysed,
radical-mediated mechanism of toxicity of the viologens
such as diquat and paraquat [1794-179 9] (whose
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herbicidal activity is in fact inhibited by iron chelators
[1800]) and of adriamycin [1801, 1802]. As mentioned
above, the carcinogenic action of asbestos may also be
due to the ability of the F e(n) that it contains to catalyse
hydroxyl radical production [1469, 1475], while carci-
nogenic mycotoxins such as aflatoxin may interact
synergistically with iron [1803].
Dietary sources of iron chelators
There is also a considerable and positive role for nutrients
in terms of t heir chelation of iron. Indeed, polyphenolic
compounds, many of which have known health benefits
[1804-1813], are widely used as food antioxidants [1814,
1815]. There is of course considerable epidemiological
evidence for the benefits of consuming f ruit and
vegetables that are likely to contain such antioxidants
(e.g. [1816-1819]), and – although possibly a minimum –
this has been popularised as the 'five a day' message (e.g.
http://www.fruitsandveggiesmatter.gov/ and http://
www.5aday.nhs.uk/). Even though elements of the
'Mediterranean'dietthatareconsideredtobebeneficial
are usually assumed to be so on the basis of their
antioxidant capabilities (but cf. [1820]), many of the
polyphenolic compounds (e.g. flavones, isoflavones,
stilbenes, flavanones, catechins (flavan-3-ols), chalcones,
tannins and ant hocyanidins) [1821 -1828] so implicated
may also a ct to chelate iron as well [1073, 1829-1843].
This is reasonable given that many o f these polyphenols
and flavonoid compounds [1821, 1844-1853] have
groups such as the catechol moiety that are part of the
known iron-binding elements of microbial siderophores.
Examples include flavones s uch as q uercetin [914, 1813,
1829, 1854-1864], rutin [1829, 1857, 1858, 1865, 1866],
baicalin [1860, 1867], curcumin [1813, 1868-1872],
kolaviron [1873], flavonol [1874], floranol [1875],
xanthones such as mangiferin [1876-1879], morin
[1876], catechins [107 3, 1807 , 1838 , 1 854, 1 880, 18 81]
and the aflavins [1882], a s well as procyanidins [1835,
1883] and melatonin [1628, 1 884-1887 ]. However, the
celebr ated (trans- )-resveratrol molecule [1888-1902] may
act mainly via other pathways.
A considerable number of studies with
non-purified
dietary constituents containing the above polyphenolic
components have also shown promise in inhibiting
diseases in which oxidative stre ss is implicated [1825,
1903-1906]. For instance in stroke and related neuronal
aging and s tress conditions, preventative activity can be
found in blueberries [1907-1913] (and see [1914]),
Ginkgo biloba extract (EGb 761) [1910 , 1915, 1916],
grapes [1917], green tea [1807 , 1918- 1921], Mangifera
indica extract [187 9], strawberries [1907], spinach [1907]
and Crataegus [922], while combinations of some these
components ('protandim') have been claimed to reduce
ROS levels by stimulating the production of catalase and
SOD [1922]. As with pharmaceutical drugs [18,
1923-1925], there are significant problems with bioa-
vailability [1926, 1927], although the necessary mea-
surements are starting to come forward [1 804, 1809,
1926-1932]. There is now increasing evidence for the
mechanisms with which these dietary c omponent s and
related natural products and derivatives (often with anti-
inflammatory, anti-mutagenic or anti-carcinogenic prop-
erties) interact with well r ecognised cellular signalling
pathways (e.g. [1402, 1935-1944, 1895 , 1945-1952,
1896, 1 410, 1953-1960, 1413, 1961-1981 , 1913, 1982,
1900, 1933, 1983-1990]).
Role of iron-generated ROSs in cellular
signalling and oxidative stress
Thus, although this is not the focus of the present more
physiologically based review, we recognise that many of
relationships between ROSs and oxidative stress and overt
progressive diseases may be me diated via the inflamma-
tory signalling pathways involved in 'innate immunity'
[900, 1991-1993]. NF-B is an important transcription
factor, and the NF-B system is intimately i nvolved in this
signalling [588, 672, 719, 1408, 1409, 1454, 1994 -2019 ].
In the NF-B system (e.g. [2020-2024]) (Fig 8), NF-Bis
normally held inactive in the cytoplasm by binding to an
inhibitor IB(oftenIBa). Pro-inflammatory cytokines
such as TNF-a, LPS [2025-2030] and IL-1 [2031] act by
binding to receptors at the cell surface and initiating
signalling pathways that lead to the activation of a
particular kinase, IB kinase or IKK. This kinase phosphor-
ylates the IB causing it to be released (and ubiquitinated
and degraded by the proteasome), allowing the NF-Bto
be translocated to the nucleus where it can activate as many
as 300 genes. Simple models of the NF-B system show the
main control elements [2032, 2033] and their synergistic
interaction [2034]. The NF-B system is implicated in
apoptosis [2035, 2036], aging [1199], and in diseases such
as cancer [1405, 1444, 1454, 1808, 2037-2040], arthritis
[2040-2043] and a variety of other diseases [2044].
Antioxidants such as vitamin E [552, 2017] and melatonin
[2045-2049] are at least partially protective. Oxidative
stress seems to act upstream of IKK [2014], on IBa
directly [2050] and in the p38 MAP kinase pathway [1993,
2014, 2051], and there is also evidence that at least some
of the statins act on the PI3K-akt and NF-Bpathwaystoo
[819, 883, 2052-2060]. A considerable number of inhibi-
tors of the NF-B system exist [2055], many exhibiting
cross-reactivity [1734].
The induction of NF-B by ROSs appears to involve a
coupling via the glutathione system [2007, 2035, 2036,
2061-2078] (and see also [2079, 2080]).
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A variety of studies have shown that iron is involved in
these signalling processes [1839, 1996, 2015,
2081-2085], probably again acting upstream of the IKK
[557, 2083, 2086, 2087].
Interestingly, there is interplay between the NF-B
pathway and the regulation of NGAL [404, 405, 2 088,
2089], ferritin [2030] and hepcidin [2090], p resumably
acting as a negative feedback as the cell tries to control
and ligand its free Fe(n) i n the face of oxidative stress
caused by the release of free iron [2091].
The systems biology of ROS generation
and activity
It is not news that most major changes in physiological
states have multigenic or multifactorial origins (e.g.
[2092, 2093]). This means, as an inevitable conse-
quence, that we ne ed to recognize that their observation
requires a systems approach, and that most diseases are
therefore in fact to be seen as systems or network
diseases [631, 2094-2102]. Changes in individual reac-
tion steps (or even single manipulations) can change the
levels of scores or hundreds of transcripts [ 2103],
proteins [2104] or metabolites [725]. In this regard,
small molecule (metabolomics) measurements have
especial advantages for capturing network organisation,
including on theoretical grounds [2105-2112].
If we consider just one variable of present relevance, the
quantity of hydroxyl radical, the amount that is able to
react with proteins, lipids and DNA is clearly determined
by a h uge n umber of reacti ons, whether dir ectly or
Figure 8
An overview of cellular signaling using the NF-Bandp38systems. Note that some of the extracellular effectors that
mediate NF-B activation are themselves produced and secreted as a result of the activation, potentially creating an
autocatalytic system.
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otherwise – not only the concentrations of reagents and
enzyme that directly catalyse its formation and destruction
but by everything else that affects
their concentration and
activity, and so on. This is of course well established in
biology in the formalism of metabolic control analysis
(MCA) (see e.g. [2113-2120]), and was recognized over 30
years ago in Morris' prescient review on anaerobes [2121].
Modern systems theories of aging (e.g. [1175, 1180, 2120,
2122] and above) (Fig 9) also recognize physiological
progression as being determined in terms of a balance
between 'good' and 'bad' factors. MCA and related
formalisms can be seen as theories of sensitivity analysis,
which in many cases can be normalized such that an overall
output function can be described
quantitatively in terms of
the relative contributions of each of its component steps (e.
g. [2123-2127]). In MCA the normalized local sensitivities
are known as control coefficients, and the sum of the
concentration-control coefficients = 0, in other words in the
steady state the rate of production and consumption of a
particular entity is in balance and
all reactions can
contribute to it to some degree. The concentration-control
coefficient describes this degree quantitatively. It is now
possible to produce appropriate quantitative representa-
tions of metabolic networks using quite sparse kinds of
information (in fact just the stoichiometry and network
structure [2128]), and thereby provide initial estimates for
more sophisticated fitting algorithms (e.g. [2129-2132].
Indeed, the analysis of the properties and behaviour of
networks is at the core of modern systems biology (e.g.
[2095, 2133-2140]).
A corollary of such considerations is that to decrease the
amount of damage caused by OH
•
(or any ot her)
radicals we need both to decrease their production and
increase their removal to harmless substances [2141],
and that on general grounds [1706-1708, 2142] such a
strategy (for instance of combining a cell-permeable iron
chelator with a cell-permeable antioxidant) might be
expected to give a synergistic response. Even determining
the means of cell permeability and tissue distribution
turns out to be a systems biology problem in which we
need to know the nature and activity of all the carriers
that are involved [18, 170 3, 1714, 2143]. At all events, i t
is undoubtedly the case that the steady-state rate of
production of a molecule such as t he hydroxyl radical is
controlled or affected by a considerable number of steps.
These minimally include the multiple reactions of the
mitochondrial respiratory chain and the various oxidases
producing superoxide and peroxide, the activities of
catalase and SOD enzymes that together can remove
them, protective reactions such as heat-shock proteins,
and most pertinently to the p resent review a large
number of reactions invol ved in the metabolism and
safe liganding of iron that help determine the rate at
which OH
•
is produced.
It is also pertinent to enquire as to why we are now
seeing so many of these progressive diseases, and as to
what may be their causes. Undoubtedly the simple fact
of improved longevity i s o ne [165] as damage accumu-
lates. However, we note that anything that decreases the
amount of unliganded iron, such as decreasing the total
dietary iron intake e.g. from red meat, must be helpful
[1156, 2144].
Anti-inflammatory cytokines; the example of
erythropoietin
We have above adduced considerable evidence that
decreasing the amount of hydroxyl radical by any means
is valuable, whether by removing initially generated
ROSs such as superoxide and peroxide or by chelating
poorly liganded iron in a way that stops these ROSs
forming the hydroxyl radical. While pro-inflammatory
cytokines can themselves increase ROS production and
modulate the activities of signaling pathways such as NF-
B and p38, there are also anti-inflammatory cytokines.
A particularly interesting exampleisthatoferythropoie-
tin (also discussed above as being protective in a number
of iron-mediated diseases).
Erythropoietin was originally recognized via its role in
erythropoiesis [2145-2147] (hence its name, of course),
but it has become evident that it has many other roles,
and in partic ular it is observed phenomenologically that
erythropoietin (and non-erthyropoetic derivatives) is
protective in a n umber of inflammatory conditions
that accompany many diseases such as those listed
above [940, 942, 2148-2155]. These included
Figure 9
General view of the role of iron, antioxidants and
ROSs in aging and degenerative processes.Someofthe
decay may be ameliorated by lifestyle and dietary means.
Based in part on [1175].
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cardiovascular disease [721, 722, 2156-2175], stroke and
other related neurological diseases [924-926, 928, 929,
933, 937, 938, 2155, 2176-2204], diabetic neuropathy
[2205], kidney injury [21 73, 2206- 2212], intest inal
injury [2213] and shock (both septic and non-septic)
[1596, 1597, 2214].
The question t hen arises as to how it is doing this
mechanistically, and the proximate answe r is that it (and
other anti-inflammatory agents, e.g. [180 8, 2215, 2216])
seem to act via many of the same signalling pathways as
do inflammatory agent s [943, 2150, 2217-2226]. There
is evidence that it can help maintain superoxide
dismutase activity [2214, 2227], invoke haem oxygenase
[2228], and in particular – from the perspective of this
review – that it may remove poorly l iganded iron [2229]
and interact with hydroxyl radical directly [2230-2233].
It is notable that appropriate levels of erythropoietin
appear not o nly to be efficacious but to be safe, even in
pregnancy [2234-2241]. Erythropoietin may it self be a
marker of hypoxia and oxidative stress in pregnancy
[531, 2242-2245], consistent with a view that the body is
attempting to deal with these problems by creating anti-
inflammatory cytokines.
Hypoxia-inducible factor (HIF)
Although I am mainly not concentrating on genetic
regulatory aspects in this review, the HIF [2246, 2247]
does deserve some mention, since many of the syn-
dromes described above are accompanied by hypoxia,
and this causes levels of the HIF to increase. HIF is a
transcription factor that can activate a considerabl e
number of genes, including VEGF [1951, 2246-2250 ].
In contrast to the constitutive expression of HIF-1a,HIF-
1b protein levels are regulated in response to the cellular
oxygen concentration [2251]. The active HIF is the HIF-
1ab heterodimer [2252]. HIF couples anoxia to innate
immunity via the NF-B system [2253]. In particular,
HIF effects (via hepcidin) the mobilisation o r iron and
can cause the expression of inflammatory cytokines such
as IL-1, IL-6 and TNF- a [2254-2256] under conditions
(hypoxia) where superoxide and peroxide production
are likely to be increased, and consequently increases
sepsis (in that HIF-knockout mice are resistant to LPS-
induced sepsis [2254, 2255]). By contrast, induction of
HIF (and the genes that it activates) can effect
neuroprotection [2252, 2 257]. H IF also appears to
have a significant role in placental development, and
defective HIF expression may be involved in pre-
eclampsia and intra-uterin e growth retardation [435,
2246, 2258]. Qutub and colleagues provide useful
models [2259, 2260] of HIF activation under a variety
of conditions of iron, O
2
, 2-oxoglutarate and other
factors.
Autocatalysis, positive feedback and Systems Biology
What has emerged in recent years is a recognition that the
structure (i.e. topology) of the modules of metabolic and
signalling networks, somewhat independent of the indivi-
dual activities of their components, can have a profound
controlling influence on their behaviour (e.g. [2107, 2134,
2135, 2261, 2262]). Classically, negative feedback structures
are considered to confer stability, while positive feedbacks
tend to have the opposite effect. However, negative
feedbacks with delay loops can cause oscillations [2022,
2109] while some kinds of positive feedback loops can
confer stability [2262, 2263]. However, there is no doubt
that structures in which a damaging agent causes the
production of a second damaging agent that itself catalyses
the production of the first or a separate damaging agent can
exhibit a runaway kind of damage. This is
exactly what can
happen with iron and superoxide since Fe(n) can be
liberated from ferritin by superoxide radicals and then
catalyse the production of further hydroxyl radical by
increasing the amount of free iron (Fig 6). A similar effect
can occur with Fe-S proteins in SOD-deficiency [1148], with
the degradation of mitochondria by radical damage leading
to further production of radicals [28, 30, 2264], and the
effects of oxidative stress on iron storage [2265]. This again
illustrates the importance of acting at multiple points in a
network to control these kinds of damage. Exactly the same
is true of the IL-1 and TNF-a systems in which IL-1 or TNF-a
(oxidative stress) acting on one cell can effect the secretion
of further IL-1/TNF-a that can act on adjacent cells (Fig 8), of
the hypoxia-dependent increase in both ROSs and serum
iron mediated by hepcidin (Fig 3), the autocatalytic synergy
between overfeeding, inflammation and (pre-)diabetes, and
of the peroxide/iron pair that are liberated when frataxin is
deficient (see above). It is these kinds of synergistic effects
and
autocatalytic cycles that are the hallmark of the major
and progressive effects on human physiology that are seen
in these kinds of system. Indeed, one might comment that
such multi-site and autocatalytic effects are required to
overwhelm normal defences precisely because human
metabolic and signalling systems are 'robust' systems that
have evolved topologies that are resistant or robust to
parameter changes (see e.g. [2266-2291]).
Predictive biology
It is often considered (e.g. [2292, 2293]) that a desirable
feature of a scientific idea is its ability to make useful
predictions, and while this is not in fact a particularly
well founded philosophical principle, it probably is of
value to set out a couple of 'predictions' that follow from
the present analysis. One prominent feature of the above
is the primacy of the iron-catalysed production of the
damaging hydroxyl radical, and thus a test of the
involvement of these kinds of reactions in the various
physiological and pathological states to which we allude
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is the prediction that t hey should be accompanied by
markers of oxidative stress characteristic of reactions of
endogenous metabolites with the hydroxyl radical.
While it is not that easy to disentangle the complex
reactions of ROSs with biomolec ules [43, 1 055], at l east
the following appear to be a result of reactions involving
OH
•
[2294, 2295]: 8-oxo-2'-deoxyguanosine (oxo
8
dG)
[98, 2296, 2297], 8-oxo-7,8- dihydro-2'-deoxyguanosine
[90, 92] and thymine glycol [92, 229 4].
Another set of predictions from the systems biology
perspective [1704-1708, 1731, 2138, 2291, 22 98-23 10]
is that combinations of chemical agents (or manipula-
tions such as those of transcription f actors that affect
multiple steps in a pathway [1906] or modulation of
multiple gene products [2311 ], or both [2312, 2313])
will be far more efficacious, for instance in modulating
iron-catalysed oxidative stress and its sequelae, than will
be the use of 'magic bullet' single agents. Such
combinations of 'causes' do not have to be guessed a
priori but can be obtained via inferencing techniques (e.
g. [2314-2320]) – for a recent exam ple see [2321]. The
nonlinear behaviour of biochemical networks also serves
to explain the bell-shaped dose-response curves under-
pinning the hormesis [2322-2326] often observed.
Iron-mediated oxidative stress is arguably the cause of
much of the inf lammation typically observed in biologi-
cal systems, often further mediated via pro-inflammatory
cytokines. Another major prediction that come s from the
above then is that molecules that are anti-inflammatory,
whether widely recognised as such or not, should have
beneficial effects in syndromes for which they have not
necessarily been tested. An obvious set of candidates in
thisregardaretobefoundamongthestatins,sinceitis
now clear that they have important anti-inflammatory
properties ( see above). Thus, there are already indications
that as well as their established benefits in cardiovascular
disease (e.g. [804, 2327]) they may exert benefit in a huge
variety of syndromes [838], including sepsis [83 9, 2060,
2328-2340], heart failure [2341 ], pain perception [2342],
lupus and related diseases [1293, 2343], diabetes [877,
2344], rheumatoid art hrit is [866, 869, 890, 2345-2350],
kidney disease [2351- 2353], inflammatory skin disease
[2354], emphysema [2355], ischaemia-reperfusion injury
[2356], stroke [864, 872, 2357-2364], traumatic brain
injury [2365-2367], neurodegenerative diseases
[860-862, 920, 1294, 2059, 2368-2384], neurotoxicity
[2385] and cancer [2386-24 00].
Concluding remarks and quo vadis
"Actually, the orgy of fact extraction in which everybody
is currently engaged has, like most consumer economies,
accumulated a vast debt. This is a debt of theory and
some of us are soon going to have an exciting time
paying it back – with interest, I hope." [2401].
"But one thing is certain: to understand the whole you
must look at the whole" [2402]
"If you are not th inking about your experime nts on a
whole-genome level you are going to be a dinosaur".
J. Stamatoyannopoulos, quoted in [2403].
While it is less common for scientists to publish
'negative' results ('there was no effect of some agent on
some process'), and there has been a tendency to seek to
falsify specific hypotheses rather than to paint a big
picture [2404], there is no doubt that the sheer weight of
positive evidence can be persuasive in leading one to a
view. As Bertrand Russell put it [2405], "When one
admits that nothing is certain one m ust, I t hink, als o
admit t hat some things are much mor e nearly cer tain
than others." However, as mentioned above, the huge
volume of scientific activity has in many ways led to a
'balkanisation' of the literatu re [2406] in which scient ists
deal with the problem of the deluge of published papers
by necessarily ignoring most of them. This is no longer
realistic (nor necessary) in an age of post-genomics, the
internet, Web 2.0 and systems biology, and when we are
starting to move to integrative (if distributed) models of
organisms (including humans) at a whole organ,
genome or whole organism scale [118, 2135,
2407-2416]. The 'digital human' is thus an important
research goal [2410, 2415-2417]. Expression profiling
atlases are becoming increasingly widespread (e.g.
[2418-2423]), and one can anticipate using these
straightforwardly to extend these 'generalised' (sub)
cellular network models in a tissue-specific manner
[2424]. With the ability t o exchange models of bio-
chemical networks in a princ ipled way [2425-2428],
when they are marked up appropriately (e.g. [3, 4]), we
can expect to begin to reason about them automatically
[118, 2429], such that we may soon look forward to an
era in which we can recognise the commonalities across
a variety of different subfields – a specific m essage of the
present overview. Thus, while iron and me tabolism
should be considered in the context of other processes
that may be contributing to the disorders discussed, and
it is evident that they are intimately involved in many
disease processes, therapies derived for one of the
inflammatory diseases listed above may well have
benefit in some of the others where their underlying
'causes' are the same. The 'mass collaboration' agenda (e.g.
[2430-2435]), in which dispersed agents contribute their
different skills to the solution of a complex problem, may
well help this happen effectively. Developments in dis-
tributed workflow technology, such as the Taverna [22-26,
2436, 2437]http://taverna.sourceforge.net/ and the
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myExperiment [2438]http://w ww.myexperiment.org/
environments, r epresent an intellectually important
approach. Important too to this endeavour will be
Open Access initiatives [1, 2439, 2440] and institutional
and other repositories [2441, 2442] of full-text papers.
This will help to build an accurate picture of the
biochemical network s operating in both normal and
diseased states (and see [2443 ]), preferably marked up
semantically as in [118], and hence, by modelling them
[2263], where best to consider inte rventions. In o rder to
develop and exploit this distributed approach, it will
also be necessary for those generating them t o m ake
their data and metadata available (preferably in a
semantically marked up way), probably as Web Services
(e.g. [24, 2444 -2452]) , and to g ive greater scientific
weight to those involved in bio-curation [119] as they
will be an increasingly important part of the scientific
landscape. Modern sequencing instruments, for instance
(e.g. [2453-2457]) are generating quality data at truly
enormous rates [2458], and innovative but computa-
tionally demanding algorithms are required t o deal with
them (e.g. [2459]). In particular, however, we need tools
for manipulating and visual ising b ioche mical m odels
[2110, 2410, 2429, 2460]. As well a s storing these
models (e.g. as SBML or C ellML [2461]) in a file format,
it is also convenient to store them in a database format,
such as the B-net database developed by Mendes and
colleagues [118, 2462]. Federated annotation protocols
such as the Distributed Annotaton Scheme (see e.g.
[2463]) allow data from heterogeneous sources to be
combined, while other integrative/distributed architec-
tures such as ONDEX [2464] and Utopia [2465-2468]
are similarly showing considerable promise for integra-
tive systems biology.
Given the widely dispersed communities that have been
referenced herein, and the future requirement for
integrating knowledge generated throughput the world,
a programme for understanding the combinatorial roles
of poorly liganded iron and reactive oxygen species in
the aetiology of many diseases, as set out in the above,
appears to be prototypical for the kinds of new
approaches to doing science t hat we may anticipate in
the eras of Web 2.0 and the Semantic Web.
Abbreviations
AECOPD: Acute Exacerbation of Chronic Obstructive
Pulmonary Disorder; AKI: Acute Kidney Injury; ALS:
Amyotrophic Lateral Sclerosis; AMD: Age-related Macu-
lar Degeneration; BBB: Blood-brain barrier; ChEBI:
Chemical Entities of Biological Interest; CQ: Clioquinol;
COPD: C hronic Obstructive Pulmonary Disorder;
DFO: Desferrioxamine; Dp44mT: di-2-pyridylketone-
4,4,-dimethyl-3-thiosemicarbazone; EDTA:
Ethylenediamine-tetraacetic Acid; F A: Friedrich's ataxia;
FPN1: Ferr oportin- 1; HBED: N,N'- bis-(2-hydroxybenzyl)
ethylenediamine-N,N'-diacetic acid; HCP1: Heme Car-
rier Protein-1; HIF: Hyp oxia-Inducible Factor; H O1:
Heme Oxygenase-1; HMG-CoA: Hydroxymethyl glutaryl
Coenzyme A; Hp: Hephaestin; 8HQs: A variety of
8-hydroxyquinolines; IBD: Inflammatory Bowel Disease;
InChI: International Chemical Identifier; IKK: IBkinase;
KEGG: Kyoto Encyclopedia of Genes and Genomes; L1:
Deferriprone;LFA-1:LeukocyteFunctionAntigen-1;LIP:
Labile Iron Pool; LIPID: Long-Term Intervention with
Pravastatin in Ischaemic Disease; LPS: Lipopolysacchar-
ide; MOF: Mult iple organ failure; NF- B: Nuclear Factor
B; NGAL: Neutrophil Gelatinase-Associated Lipocalin
(Also k nown as lipocalin-2 or siderocalin); NIH:
2-hydroxy-1-napthylaldehyde isonicotinyl hydrazo ne;
PE: Pre-eclampsia; PIH: Pyridoxal isonicotinyl hydra-
zone; PPAR: Peroxisome Proliferator Activated Receptor;
RA: Rheumatoid Arthritis; ROS: Reactive Oxygen Species;
SBML: Systems Biology Markup Language; SIH: Salicy-
laldehyde isonicotinyl hyd razone; SIRS: Systemic Inflam-
matory Response Syndrome; SLE: Systemic Lupus
Erythematosus; SMILES: Simplified Molecular Input
Line Entry Specif ication; SOD: Superoxide Dismut ase;
Tf:Transferrin;TNF:TissueNecrosisFactor;VEGF:
Vascular Endothelial Growth Factor.
Competing interests
The author declares t hat he has no competing interests.
Acknowledgements
I thank Jon Barasch (Columb ia University) for drawing my attention to the
role of NGAL in human physiology, and Phil Baker, David Brough and
Louise Kenny for many further useful and enjoyable discussions. I thank
Katya Tarasova for considerable assistance with literature gathering and
Julie Cowley for assistance with the proofs. Much of my work when this
was written has been supported by the UK BBSRC and EPSRC, for which I
am most grateful, and I am also a recipient of funding from the British
Heart Foundation. The funders ha d no role in study design, d ata collection
and analysis, decision to publish, or preparation of the manuscript. This is a
contribution from the Manchest er Centre for Integrat ive Systems Biology
http://www.mcisb.org.
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