ArticlePDF AvailableLiterature Review

Risks of Copper and Iron Toxicity during Aging in Humans

Authors:

Abstract

Copper and iron are essential but also toxic metals. Their essentiality is known, but their toxicity, except for the genetic overload diseases, Wilson's disease and hemochromatosis, is not so well known. Yet, their toxicities are so general in the population that they are a looming public health problem in diseases of aging and in the aging process itself. Both metals are transition elements, and their resulting redox properties have been used during evolution in the development of oxidative energy generation. But both contribute to the production of excess damaging oxidant radicals. Evolution has kept stores of copper and iron in excess during the reproductive years because they are so vital to life. But the oxidant damage from these excess stores of metals builds up as we age, and natural selection ceases to act after about age 50 since diseases after that do not contribute to reproductive fitness. Diseases of aging such as Alzheimer's disease, other neurodegenerative diseases, arteriosclerosis, diabetes mellitus, and others may all be contributed to by excess copper and iron. A very disturbing study has found that in the general population those in the highest fifth of copper intake, if they are also eating a relatively high fat diet, lose cognition at over three times the normal rate. Inorganic copper in drinking water and in supplements is handled differently than food copper and is therefore more toxic. Trace amounts of copper in drinking water, less than one-tenth of that allowed in human drinking water by the Environmental Protection Agency, greatly enhanced an Alzheimer's-like disease in an animal model. In the last part of this review, I will provide advice on how to lower risks from copper and iron toxicity.
Risks of Copper and Iron Toxicity during Aging in Humans
George J. Brewer*
Departments of Human Genetics and Internal Medicine, UniVersity of Michigan Medical School,
Ann Arbor, Michigan
ReceiVed September 17, 2009
Copper and iron are essential but also toxic metals. Their essentiality is known, but their toxicity,
except for the genetic overload diseases, Wilson’s disease and hemochromatosis, is not so well known.
Yet, their toxicities are so general in the population that they are a looming public health problem in
diseases of aging and in the aging process itself. Both metals are transition elements, and their resulting
redox properties have been used during evolution in the development of oxidative energy generation.
But both contribute to the production of excess damaging oxidant radicals. Evolution has kept stores of
copper and iron in excess during the reproductive years because they are so vital to life. But the oxidant
damage from these excess stores of metals builds up as we age, and natural selection ceases to act after
about age 50 since diseases after that do not contribute to reproductive fitness. Diseases of aging such as
Alzheimer’s disease, other neurodegenerative diseases, arteriosclerosis, diabetes mellitus, and others may
all be contributed to by excess copper and iron. A very disturbing study has found that in the general
population those in the highest fifth of copper intake, if they are also eating a relatively high fat diet, lose
cognition at over three times the normal rate. Inorganic copper in drinking water and in supplements is
handled differently than food copper and is therefore more toxic. Trace amounts of copper in drinking
water, less than one-tenth of that allowed in human drinking water by the Environmental Protection
Agency, greatly enhanced an Alzheimer’s-like disease in an animal model. In the last part of this review,
I will provide advice on how to lower risks from copper and iron toxicity.
Contents
1. Introduction 319
1.1. Oxidant Damage and the Role of Copper and Iron 319
2. Contribution of Copper and Iron Toxicity to Specific
Diseases of Aging
320
2.1. Copper and Alzheimer’s Disease 320
2.2. Copper and Other Diseases of
Neurodegeneration
321
2.3. Copper and Cognition in the General Population 321
2.4. Copper and Atherosclerosis 321
2.5. Copper and Diabetes 321
2.6. Copper and Other Diseases 321
2.7. Iron and Atherosclerosis 322
2.8. Iron and Alzheimer’s Disease 322
3. Oxidant Damage Theory of Aging and the Role of
Copper and Iron
322
4. What Can Be Done to Minimize Copper and Iron
Toxicity?
322
4.1. Avoid 322
4.2. Measure 323
4.3. Intervene 323
4.4. Monitor 323
1. Introduction
I was very pleased to be invited to contribute a paper to this
issue of Chemical Research in Toxicology, on metal toxicity,
because I think there is an important story to tell about copper
and iron toxicity. This story, which I think is reaching the level
of public health significance, is virtually unknown to the general
medical community, to say nothing of the complete unawareness
of the public. I have written on this topic before (1–3), but this
review gives me the chance to put all the pieces together. In
addition, I am coauthoring a book on this topic, which has been
recently published (4).
When we think of metal toxicity, most of us think of the
villains, such as lead and cadmium. Not so much do we think
of the good guys, the essential metals, such as copper and iron,
that make essential contributions to our lives. Of course,
physicians are aware of copper and iron toxicities in Wilson’s
disease and hemochromatosis, respectively, where the body is
grossly overloaded with these metals. But in this review, I want
to tell the story of the more subtle toxicity of copper and iron
that does not just affect a limited number of us, as with Wilson’s
disease and hemochromatosis, but may affect almost all of us
as we age.
I will tell the story in four parts. In the first part, I will review
oxidant damage, and the mechanism of copper and iron toxicity,
which involves oxidant damage. In the second part, I will review
the contribution of copper and iron toxicity to specific diseases
of aging, such as Alzheimer’s disease (AD) and atherosclerosis.
In the third part, I will review oxidant damage as a likely
component of aging in general, and the likely contribution of
copper and iron toxicity to aging. In the fourth part, I will discuss
what can be done to minimize copper and iron toxicity, including
some of our own research.
1.1. Oxidant Damage and the Role of Copper and Iron.
Higher organisms, such as ourselves, live in the fast lane in
that we use oxygen to fuel a very high level of energy
generation. Much of this oxidative metabolism occurs in the
mitochondria of cells where high energy phosphate bonds are
created in the form of adenosine triphosphate (ATP). Nutrients
and oxygen are utilized in this process. Toxic byproducts of
this metabolism are generated, called reactive oxygen species
* To whom correspondence should be addressed. E-mail: gjbrewer@
umich.edu.
Chem. Res. Toxicol. 2010, 23, 319–326 319
10.1021/tx900338d 2010 American Chemical Society
Published on Web 12/07/2009
(ROS). These include the superoxide anion, singlet oxygen,
hydrogen peroxide, and the hydroxyl radical. ROS can cause
damage to most biological molecules, including DNA, protein,
and lipids, resulting in damage to membranes and various
cellular organelles. The reviews by Poon et al. (5) and Butterfield
and Kanski (6) are quite instructive as to the mechanisms of
oxidant damage.
Cells have defenses against ROS, enzymes that scavenge and
destroy these molecules. These include the enzymes catalase,
superoxide dismutase, glutathione peroxidase, glutathione trans-
ferase, and others. However, these defenses are not perfect, and
some ROS escape and cause continual damage.
Copper and iron are essential elements, necessary for life.
Good reviews of the importance of copper and iron for life are
given in refs 7and 8, respectively. They are important
components of many proteins and many enzymes, including
many that participate in the generation of high energy metabo-
lites. In other words, copper and iron are integral components
of what allows us to live in the fast lane. This is the good guys
side of these metals.
But both copper and iron have their dark side, their toxic
side. They are both transition elements. A characteristic of
transition metals is that they exhibit two or more oxidation states.
The oxidized states are Cu2+and Fe+++, and the reduced states
are Cu+and Fe2+. This redox capability is what makes them
useful in various steps of energy generation. But it is also what
allows them to catalyze the generation of damaging ROS.
Copper and iron are particularly damaging when they exist
in what we will loosely call their free state. Explaining this
further, starting with copper, 85-95% of the copper in human
blood is safely covalently bound to a molecule called cerulo-
plasmin (Cp). The other 5-15% is loosely bound to albumin
and small molecules in the blood. This 5-15% pool is what
we call free copper, although it is actually loosely bound. The
free copper is available to meet cellular needs, for example, for
incorporation into enzymes. This free copper is also available
to cause toxicity such as the generation of ROS. The evidence
indicates that the larger this pool of free copper, the greater the
damage that is produced. For example, in Wilson’s disease, this
free copper pool in the blood is greatly expanded (9). Whereas
normal people have 5-15 µg/dL of free copper, untreated
Wilson’s disease patients may have 50 µg/dL or higher and as
a consequence suffer severe damage to their liver and/or their
brain. I will present evidence that those normals living on the
high side of the 5-15 µg/dL normal range may also be suffering
from more subtle copper toxicity.
Another important piece of information about copper is that
organic copper, that is, food copper where the copper is bound
to proteins, is handled differently by the body than inorganic
copper consumed in drinking water or mineral supplements (2).
Food copper is processed by the liver, which does not allow
excess release into the free copper pool in the blood. Inorganic
copper in large part bypasses the liver and contributes im-
mediately to the free copper pool in the blood. For example,
when we give an oral dose of radioactive 64Cu as an inorganic
salt, a substantial part of the 64Cu appears in the blood almost
immediately, having bypassed liver metabolism (10). This
inorganic copper contributes immediately to the free copper
pool. This becomes important when we discuss later the negative
effects of copper in drinking water and the copper in vitamin/
mineral supplements on cognition and on Alzheimer’s disease.
Turning to iron, it is primarily carried by molecules in the
blood called transferrin and ferritin. Transferrin is a molecule
that delivers iron to meet cellular needs. The percent transferrin
saturation is one measure of iron adequacy, and the normal range
is 15-45% in both men and women. Ferritin is a storage
molecule for iron. Its normal value is different between men
and women because during menstruation, women lose consider-
able iron, and their storage iron is reduced. Menopausal women
begin to catch up with men. The normal serum ferritin range
for men is 15-320 mg/mL and for women is 6-155. The actual
observed mean values on a large sample of people, as reported
by Zacharzski et al. (11) from National Health and Nutrition
Examination Survey (NHANES) III data, are about 150 for men,
about 30 for menstruating women, and about 60 for menopausal
women. I will present evidence that the higher the available
iron, in other words the free iron, the greater the risks of
developing important diseases of aging.
In considering the roles of copper and iron toxicity in humans,
it is important to simultaneously consider the role of evolution
(1, 4). Evolution promotes fitness, which is measured by success
in reproduction. Adequate copper and iron are important for
successful reproduction because they are so important to life.
If an individual has extra stores of copper and iron, they are
partially protected against negative events such as lack of food
and trauma leading to blood loss, and increased need of nutrients
for wound repair. Thus, evolution has favorably selected
individuals with extra stores of these metals because they are
more likely to successfully reproduce, i.e., they are more fit. If
these extra stores of copper and iron cause some toxicity during
the reproductive years, it does not affect fitness as long as it
does not produce a disease during the reproductive years. The
reproductive years in humans are perhaps up to age 50, when
one considers that good health in the parents during early care
giving years to the children is also important in reproductive
success.
But after about age 50, natural selection ceases to act against
diseases in humans because they no longer affect successful
reproduction. Thus, there is no natural selection against diseases
of aging. In addition, there is no natural selection against having
too high and toxic levels of free copper and iron, as long as
those levels were acceptably safe during the reproductive years.
Thus, it is my view that the levels of copper and iron we
consider normal for humans are acceptable during the reproduc-
tive years but are, on average, too high after age 50 and
contribute to diseases of aging.
2. Contribution of Copper and Iron Toxicity to
Specific Diseases of Aging
2.1. Copper and Alzheimer’s Disease. When Sparks and
colleagues moved their research activities from one laboratory
to another, they were frustrated when they could not reproduce
their results in the second location (12). They were studying a
rabbit model of Alzheimer’s disease (AD) in which rabbits fed
a high cholesterol diet developed Alzheimer’s-like amyloid
plaques in the brain and lost cognition, that is, they had a fall
off in performance of certain tasks. In the new location, the
whole disease process was much more mild. They finally
realized that the rabbits in the new location were given distilled
water to drink, while in the old laboratory, they were given tap
water. They carefully evaluated what it was in tap water that
made the difference and determined that it was trace amounts
of copper. They then did studies where they showed that 0.12
ppm (parts per million) of copper in distilled water used for
drinking had a dramatic effect in increasing amyloid plaques
and decreasing cognitive performance in the AD rabbit model
(12). The Environmental Protection Agency (EPA) allows over
10 times (1.3 ppm) that much copper in human drinking water
320 Chem. Res. Toxicol., Vol. 23, No. 2, 2010 Brewer
(13). These rabbit model results should give us strong warnings
that we may be worsening AD in human patients by having
too much copper in our drinking water. The reader should recall
our earlier discussion that inorganic copper, like the copper in
drinking water, partially bypasses the liver and contributes
directly to the free copper pool in the blood.
A group at the University of Rochester has done a study
which provides a mechanism whereby low levels of free copper
in the brain could be toxic in AD (14). They find that 0.12 ppm
copper damages low density lipoprotein receptor-related protein,
a molecule responsible for efflux of β-amyloid from the brain.
β-Amyloid is the protein that forms amyloid plaques, one of
the hallmarks of the AD brain.
It is of interest and of possible importance that all of the
molecules known to be involved with pathology in the AD brain
are binders of copper. This is true of the amyloid precursor
protein (APP), which has a copper binding domain that reduces
Cu++ to Cu+and then produces oxidative damage (15, 16). This
is also true of the β-secretase enzyme that cleaves β-amyloid
from APP (17) and the β-amyloid itself, which binds copper
and cholesterol, facilitating copper oxidation of cholesterol to
7-OH cholesterol, extremely toxic to neurones (18, 19). It is
also true of the τ-protein that forms the neuro-fibrillary tangles,
another hallmark of the pathology in the AD brain (20). Amyloid
plaques and neuro-fibrillary tangles are major sites of catalytic
redox activity (21). This redox activity is abolished by desfer-
rioxamine, an iron chelator, or by EDTA, a general metal
chelator, and is restored with copper or iron replenishment. The
copper binding by all these proteins does not prove that copper
is causative or even a risk factor for AD, but it helps increase
suspicion that copper dyshomeostasis could be playing a role.
Rosanna Squitti and her colleagues (22) in Italy have found,
importantly, that free copper levels are elevated in the blood of
AD patients compared to age-matched controls. They have also
found that a measure of cognition in AD, the mini-mental state
examination (MMSE), correlates negatively with free copper
levels in AD (23). In other words, the higher the free copper,
the lower the cognitive ability. Furthermore, they later showed
that free copper levels were a predictor of annual decline in
mini mental state examination (MMSE) values in AD patients
(24).
Certain risk factors for AD are connected with copper. The
ApoE protein has three alleles, ApoE2, ApoE3, and ApoE4.
ApoE4 is a risk factor for AD, while ApoE2 is protective (25).
ApoE2 has two copper binding cysteines at a copper binding
location, while ApoE3 has one and ApoE4 none. Thus, the
increased risk of AD for ApoE4 genotypes may relate to the
inability of ApoE4 to bind copper and remove it from the brain.
Another molecule that is a risk factor for AD and also
interacts with copper is homocysteine. Elevated homocysteine-
levels are a risk factor for the development of AD (26).
Homocysteine interacts with copper to produce increased oxidant
stress and oxidizes low density lipoprotein (LDL) that contrib-
utes to the development of AD (27).
Not all authors agree that excess copper is involved in the
pathogenesis of AD. Here, I cite authors with a contrary opinion
(28–30).
2.2. Copper and Other Diseases of Neurodegeneration.
Parkinson’s disease, Huntington’s disease, amyotrophic lateral
sclerosis (Lou Gehrig’s disease), and prion diseases such as
Jacob-Crutczfeld disease, are all diseases of neurodegeneration.
All have misfolded proteins that form inclusion bodies. The
formation of these inclusion bodies is copper dependent (31).
Additionally, we have found an elevated blood free copper level
in Parkinson’s disease patients (32). There are tantalizing bits
of evidence in various diseases suggesting free copper involve-
ment (33–37).
2.3. Copper and Cognition in the General Population. Dr.
Martha Morris and co-workers in Chicago have done a very
important study in the general population (38). They looked at
the intake of various foods and micronutrients such as copper
in a large sample of people and looked at decline in cognition
over a six year period. They found that those people in the
highest quintile of copper intake, if they also consumed a high
fat diet, lost cognition at a rate of 19 years in a six year period.
In other words, they lost cognition at over three times the rate
expected!
These people were in the highest quintile of copper intake
primarily because they took copper in their vitamin/mineral
supplement pill. These data are frightening! Almost all vitamin/
mineral supplements contain copper. Copper deficiency is
extremely rare; therefore, almost no one needs copper supple-
ments, yet tens of millions of people are taking copper
supplements and in my view are running the risk of poisoning
themselves with copper.
2.4. Copper and Atherosclerosis. I have previously sum-
marized the evidence that copper is involved in atherosclerosis
(1). The best evidence is probably the interaction of copper and
homocysteine to generate oxidant stress and oxidize LDL, which
is a component of the atherosclerotic plaque (27, 39–42).
Elevated homocysteine levels are a known risk factor for
atherosclerosis (as well as AD), and it may be this toxic
interaction with copper that makes it a risk factor.
There is also epidemiologic evidence supportive of an
association of elevated copper and/or ceruloplasmin (Cp) levels
with atherosclerotic disease (data reviewed in ref 1). One of
the coppers of Cp can interact with LDL and oxidize it, thus
generating oxidized LDL, which, as we have said, is a
component of the atherosclerotic plaque (43–45). A rabbit model
study of atherosclerosis found that at high (as well as low) levels
of copper supplementation, atherosclerosis was enhanced (46).
The evidence that iron promotes atherosclerosis, which we
will discuss shortly, is very good. Since both iron and copper
promote oxidant stress, a positive role for iron supports the
concept of a positive role for copper.
2.5. Copper and Diabetes. Cooper and colleagues (47) have
shown abnormal copper metabolism in a rat model of diabetes,
and diabetic rats with heart failure were greatly improved by
treatment with the anticopper drug, trientine. They followed
these animal studies up with clinical studies in which left
ventricular hypertrophy in diabetic patients was reduced by
trientine therapy (47). Eaton and Qian (48) have found in an
animal model that copper interacts with glycated proteins and
produces neuropathy, one of the complications of diabetes in
humans.
2.6. Copper and Other Diseases. Copper has been suggested
as a factor in several other diseases (4). Free copper is elevated
in Parkinson’s disease (49). Free copper may be elevated in
autism and Tourette’s syndrome. Drusen in age related macular
degeneration requires copper for formation (4, 50).
So far, not much has been published about copper and cancer
risk, but since it promotes oxidative stress and inflammation, it
is likely that it could play a role, such as in prostate cancer for
which inflammation is important. Thus, we suspect the study
reported by Zhang et al. (51), in which they reported zinc use
for 10 years or more, either in a multivitamin preparation or as
a supplement, increased the risk of prostate cancer, is in error.
Zinc is an anti-inflammatory, antioxidant agent (52) and would
ReView Chem. Res. Toxicol., Vol. 23, No. 2, 2010 321
be expected to be protective as reported by Hu and Song (53),
and by Gonzalez et al. (54). The latter study evaluated 35,242
men and found that supplemental zinc of 15 mg or more
significantly protected against advanced prostate cancer. Thus,
it may well be that the other components, such as copper, in
the multivitamin preparation taken in the Zhang et al. (51) study
are the real culprits.
2.7. Iron and Atherosclerosis. Sullivan was the first to
propose (55) and has continued to reiterate (56, 57) that iron
levels play a major role in producing atherosclerosis. His major
basis for this proposal was that menstruating women, who have
a reduced iron load as a result of blood loss, have strong
protection against atherosclerosis, compared to men in the same
age group. Post-menopausal women lose this protective effect.
It has been clearly shown that the protective effect of menstrua-
tion is not due to hormonal effects (58–61).
There is some positive epidemiological data correlating some
measure of atherosclerosis with some measure of iron stores,
such as serum ferritin or transferrin saturation (reviewed in ref
62). There are also positive studies of blood donors having less
atherosclerotic disease (reviewed in ref 62). Other types of
evidence are discussed in my previous review (1).
One problem with the iron hypothesis of Sullivan has been
that homozygous hemochromatosis, in which iron loading is
severe, has not been associated with a greater amount of
atherosclerosis. Recently, Sullivan (63) has explained this. There
is a very low level of hepcidin in homozygous hemochromatosis.
Hepcidin promotes iron accumulation in macrophages. Iron
laden macrophages are a key factor in the development of
atherosclerotic plaques and in the instability of the plaques,
promoting their rupture. These events lead to clot formation
and vascular occlusion. In the absence of hepcidin, there are
no iron laden macrophages to promote the development of
atherosclerotic lesions. This explanation offered by Sullivan (63)
seems to nicely explain the lack of excess atherosclerosis in
hemochromatosis in spite of the iron loading in this disease.
2.8. Iron and Alzheimer’s Disease. This area has been
reviewed by Ong and Halliwell (64), who suggest that an
important mechanism is the interaction of iron and cholesterol
in promoting oxidative damage, causative of both atherosclerosis
and neurodegeneration. Another important type of evidence is
that mutations in genes involved in controlling iron predispose
to AD (65). Thus, mutations in the hemochromatosis gene, HFE,
increase the risk of AD (66), and patients with the transferrin
subtype C2 also have an increased risk (67–69). The presence
of both of these increases the risk of AD 5-fold (70). A clinical
trial of the iron chelator, desferrioxamine, given for two years
to AD patients, clearly slowed the clinical progression of
dementia (71).
3. Oxidant Damage Theory of Aging and the Role of
Copper and Iron
Harman has been an early proponent of the oxidant damage
theory of aging (72, 73). The concept proposes that the constant
production of toxic free radicals, particularly reactive oxygen
species, slowly produces mitochondrial damage. The slow loss
of mitochondria and their energy production is associated with
aging and may be a major cause of aging. Free iron and free
copper, the greater their levels, accelerates the production of
toxic radicals. Several reviews on this topic, particularly
regarding iron, have been published (5, 6, 8, 65, 74–77).
Lowering total iron has increased the life span of fruit flies (78)
and houseflies (79).
Transferrin saturation has been linked to overall mortality in
the NHANES I study. People with a transferrin saturation over
55% (1-2% of the population) had increased mortality (80).
Also, those with elevated transferrin saturation had increased
mortality if they had high iron or red meat intake (81). Thus, it
is possible, perhaps even likely, that the toxicity of free copper
and free iron extends to the very basic process of aging itself.
4. What Can Be Done to Minimize Copper and Iron
Toxicity?
4.1. Avoid. The first recommendation under Avoid is very
simple. Simply avoid taking in supplements containing copper
and iron. Most multivitamin/multimineral pills have copper, and
this copper is potentially dangerous, as we have described. Scan
the label on your supplement bottle, and stop taking it if it
contains copper. Copper deficiency is extremely rare, and almost
no one needs copper. Keep in mind that those in the highest
quintile of copper intake, in the Morris et al. study (38), those
that were losing cognition at over 3 times the normal rate, got
there for the most part by taking copper supplements.
Men rarely need iron supplements unless they have chronic
blood loss. But some menstruating girls and women, particularly
if menstrual flow is heavy, may become iron deficient. However,
the patient should consult with her doctor to see if iron
supplementation is necessary.
The second recommendation under Avoid is harder and
requires a lifestyle change, and that is to lower the consumption
of meat. Both copper and iron are much more bioavailable from
meat than from vegetable foods (82, 83). That means that these
metals are much more easily absorbed from meat sources. Liver
and shellfish are particularly high in copper content. Red meat
is particularly high in bioavailable iron. But copper and iron
are readily bioavailable from all meat foods.
There are no good data on how much one needs to reduce
meat intake to have a desirable effect on copper and iron levels.
There is evidence on mortality. According to the NIH-AARP
(American Association of Retired Persons) study (84, 85), those
who averaged 2/3 of an ounce of red meat/day had 30% less
mortality than those who averaged 5 ounces of red meat/day.
Processed meats also increased mortality. Mortality was 20%
higher in those who averaged 2 ounces of processed meat per
day (an average of one hot dog/day), compared to those who
ate almost 15% that much. It is possible that the reduction in
mortality seen in the study is at least partially due to the
reduction of copper and iron intake.
So far, one can follow my recommendations without measur-
ing anything, but to follow our third recommendation under
Avoid, which is avoid drinking water with elevated copper
content, one has to measure the copper in their drinking water.
Eighty percent of homes in the U.S. have copper water pipes.
Whether toxic amounts of copper leaches from the copper pipes
depends mostly on the acidity of the water. The more acidic
the water, the more copper leaches from the pipes. Also, if the
plumbing system is used as the electrical ground for the house
(which is legal in many places, but should not be), more copper
can leach from the pipes.
There are various laboratories where copper in the water can
be measured. It is best to measure both the first draw water in
the morning and water after allowing the tap to run for five
minutes. Because stagnant water may contain more copper, it
is good to know if this is the case so that it can be avoided if
necessary. Since 0.12 ppm (parts per million) caused worsening
in Alzheimer’s-like disease in the rabbit model (12), we
recommend the drinking water contain no more than about 0.01
322 Chem. Res. Toxicol., Vol. 23, No. 2, 2010 Brewer
ppm. (The EPA allows 1.3 ppm!) If the drinking water contains
too much copper, a reverse osmosis device can be installed on
the tap used for drinking and cooking water. Alternatively,
distilled water, which contains no copper, can be purchased for
drinking and cooking. Bottled waters, which many people now
drink, are an unknown for copper content, and at this point
cannot be used to avoid copper in drinking water.
If one wishes to go further in limiting risks from free copper
and iron, one will have to follow steps in the section entitled
Intervene. In order to do this, certain measurements of copper
and iron status have to be made. These will require the
participation of one’s doctor to draw blood and order tests.
4.2. Measure. Free copper levels in the blood can be
determined by measuring serum copper and serum ceruloplasmin
(Cp) on the same sample. It is best to measure Cp by the oxidase
method, although most clinical laboratories measure it by an
immunologic method, which will have to do if the other method
is not available. The copper in the Cp molecule is subtracted
from the serum copper to determine the free copper. Each mg
of Cp contains 3 µg of copper. An example calculation is as
follows. A typical Cp value might be 25 µg/dL of serum.
Multiplied by 3, this equals 75 µg/dL of copper in Cp. A typical
value for serum copper is 90 µg/dL. Subtracting 75 from 90
equals 15 µg/dL of free copper. The normal range is 5-15 µg/
dL. Because of built in bias in Cp values determined im-
munologically, occasional values of free copper will be very
low or even below zero. This is acceptable; it simply means
that the free copper value is low.
The iron variables to be measured are serum iron, percent
transferrin saturation, and ferritin. These are standard tests which
can be simply ordered.
4.3. Intervene. The intervention steps reviewed here are a
more aggressive approach to copper and iron control. Whether
one wishes to be more aggressive is an individual choice, partly
based upon how one views the risks I have described and after
discussion with a doctor. I believe these risks should be taken
seriously. I view the situation as being similar to cigarette
smoking. Those who stopped when risks were emerging but
before definitive proof was developed accomplished much in
risk avoidance.
Regarding copper, those in the upper half of the free copper
distribution, after stopping supplements, lowering meat intake
as much as is acceptable, and avoiding elevated levels of copper
in drinking water, may wish to take the next step. The
intervention step required to further lower free copper is to take
oral zinc supplements. As we have shown when we developed
zinc as an FDA-approved therapy for Wilson’s disease, a disease
of copper accumulation and copper toxicity, zinc therapy will
lower free copper levels (86). It does so by inducing intestinal
cell metallothionein, which acts to strongly limit copper
absorption. The minimal dose of zinc to do this is about 40 mg
twice a day. Two daily doses are required to keep metallothio-
nein induced. The zinc dose must be separated from food and
beverages other than water by at least 1 h before and 2 h after.
The starting dose might be 50 mg twice per day, to lower
free copper to less than 7 or 8 µg/dL. Free copper should be
measured at baseline and after 3 months and then monthly while
on this dose. As soon as the free copper gets down to target
range, the dose should be reduced to say 25 mg twice per day
or, if necessary, 25 mg in the morning and 50 mg in the evening.
The dose should be adjusted to lower free copper as necessary.
The Cp value is a safety factor. If it starts to go down, say to
20% less than baseline, one is overshooting and should reduce
the dose of zinc. If the Cp goes down substantially, one is
running the risk of copper deficiency, which if it becomes severe,
can be serious. Zinc can be purchased over the counter in
pharmacies and health food stores. The best salts are zinc acetate
and zinc gluconate. It is safest to take zinc with the supervision
of one’s doctor.
Another type of data to keep in mind when deciding to lower
free copper is that we have shown in multiple animal model
studies that lowering free copper levels is beneficial in fibrotic,
inflammatory, and autoimmune disease processes (87). This was
done primarily with a more potent anticopper drug, tetrathio-
molybdate, but zinc therapy was also effective (88). Again, zinc
is best taken with the supervision of one’s doctor.
Regarding iron, one might use the percent transferin saturation
in the same way that the free copper levels are used. The normal
range is 15-45% in both men and women. Those higher than
about 25% might choose to intervene. Serum ferritin can also
be used. The normal range for men is 18-320 ng/mL and for
women is 6-155 ng/mL. The average values for men is about
150 and is about 30 for menstruating women, and about 60 for
menopausal women.
The intervention for lowering free iron is blood donation or
removal of a significant amount of blood on a regular basis. It
is probably not necessary for menstruating women to intervene
in this manner because of their monthly blood loss. But men
and menopausal women could donate 500 mL of blood every
2 months (or have that much removed if they are not suitable
blood donors), until their percent transferrin saturation is in the
15-25 range. They could also attempt to lower serum ferritin
to 50 or below. It would probably take a year or two of regular
(at least every 2 months) blood donations, particularly for men,
to reach this goal.
4.4. Monitor. I have already covered this to a certain extent
in the previous section, but I will expand on it a little here. If
one is going to intervene by taking zinc to lower free copper
and or donate blood to lower free iron, it is important to monitor
free copper and/or free iron levels.
In the case of copper, because zinc acts slowly, it is not
necessary to check free copper (and Cp) levels until three
months. After that, it should be checked monthly until a stable
maintenance dose is reached. After that, monitoring can occur
every three months and later every six months to make sure
that things are staying on track.
In the case of iron, blood donation (or blood letting) will
have a slow effect. Iron variables can be measured everly six
months for monitoring purposes.
In summary, it appears very likely that copper and iron
toxicity are occurring, but in somewhat subtle ways, in a large
proportion of our population. Both copper and iron toxicity are
likely contributing to Alzheimer’s disease (AD). There is a major
epidemic of AD in the industrialized world. Careful research
by Waldman and Lamb (89) has shown that this disease did
not exist until 100 years ago. It still is rare in India and Africa.
There is something about industrialization that has brought this
disease on in the developed world in epidemic proportions.
Waldman and Lamb (89) think it is due to the consumption of
beef because they think it is a prion disease. I think it may be
due, in part, to increased meat ingestion because of the increased
bioavailability of copper and iron from meat, but may also be
due in part to the increased use of copper pipes for plumbing
in developed countries and the increased ingestion of copper
supplements.
Another major disease is atherosclerosis, likely contributed
to by both copper and iron toxicity. Atherosclerosis causes heart
disease and stroke, the leading causes of death. Diabetes mellitus
ReView Chem. Res. Toxicol., Vol. 23, No. 2, 2010 323
is also epidemic, mostly due to the epidemic of obesity, but the
disease and its complications are likely contributed to by copper
toxicity.
Parkinson’s disease, another disease which appears to be
related to development, also is characterized by a high free
copper level. Perhaps it owes its increasing frequency to
increased free copper exposure. Many other diseases we have
discussed here (and some we have not, such as autism), may
be contributed to and owe their increased frequency to increased
free copper and/or iron exposure.
The process of loss of cognition during aging may be greatly
speeded up by increased free copper exposure, as suggested by
the work of Morris, et al. (38), and the very process of aging
itself, if due to a lifetime of oxidant stress (72, 73), is likely
increased by higher levels of free copper and free iron since
the toxicities of these two metals is through the production of
oxidant stress.
I have provided some relatively simple ways of lowering the
risks of free copper and iron, by throwing away supplements
containing these metals, by lowering meat intake, and by
avoiding drinking water with elevated levels of copper. I have
also reviewed more rigorous methods of lowering free copper
and free iron exposure, by taking zinc to lower copper and using
blood donation to lower iron. These latter steps are not medical
advice (for which one should see one’s doctor) but are simply
information to use or not use as one sees fit.
It seems clear that large segments of the population are at
risk for toxicities from free copper and free iron, and to me, it
seems clear that preventative steps should begin now.
References
(1) Brewer, G. J. (2007) Iron and copper toxicity in disease of aging,
particularly atherosclerosis and Alzheimer’s disease. Exp. Biol. Med.
(Maywood) 232 (2), 323–35.
(2) Brewer, G. J. (2008) The risks of free copper in the body and the
development of useful anticopper drugs. Curr. Opin. Clin. Nutr. Metab.
Care. 11, 727–732.
(3) Brewer, G. J. (2007) Elevated levels of dietary copper may accelerate
cognitive decline and hasten the onset of Alzheimer disease. Nutr.
M.D. 33,1-4.
(4) Brewer, G. J., and Newsome, D. A. (2009) How Chronic Copper
Toxicity Is Causing the Epidemic of Alzheimer’s Disease and Dementia
(Brewer, G. J., Ed.) George J. Brewer, Inc., Ann Arbor, MI.
(5) Poon, H. F., Calabrese, V., Scapagnini, G., and Butterfield, D. A.
(2004) Free radicals and brain aging. Clin. Geriatr. Med. 20, 329–
359.
(6) Butterfield, D. A., and Kanski, J. (2001) Brain protein oxidation in
age-related neurodegenerative disorders that are associated with
aggregated proteins. Mech. Ageing DeV. 122, 945–962.
(7) Brewer, G. J., Harris, E. D., and Askari, F. K. (2007) Normal Copper
Metabolism and Lowering Copper to Subnormal Levels for Thera-
peutic Purposes, in Textbook of Hepatology: From Basic Science to
Clinical Practice (Benhamou, J. P., Rizzetto, M., Reichen, J., Rodes,
J., and Blei, A. , Eds.) Blackwell Publishing, Oxford, England.
(8) Weinberg, E. D. (2004) Exposing the Hidden Dangers of Iron,
Cumberland House Publishing, Inc, Nashville, TN.
(9) Brewer, G. J., Askari, F., Dick, R. B., Sitterly, J., Fink, J. K., Carlson,
M., Klein, K. J., and Lorincz, M. T. (2009) The treatment of Wilson’s
disease with tetrathiomolybdate(TM). V Control of free copper by
TM and a comparison with trientine. Transl. Res. 154, 70–77.
(10) Hill, G. M., Brewer, G. J., Juni, J. E., Prasad, A. S., and Dick, R. D.
(1986) Treatment of Wilson’s disease with zinc. II. Validation of oral
64copper uptake with copper balance. Am. J. Med. Sci. 12, 344–349.
(11) Zacharski, L. R., Ornstein, D. L., Woloshin, S., and Schwartz, L. M.
(2000) Association of age, sex and race with body iron stores in adults:
analysis of NHANES III data. Am. Heart J. 140, 98–104.
(12) Sparks, D. L., and Schreurs, B. G. (2003) Trace amounts of copper in
water induce beta-amyloid-plaques and learning deficits in rabbit model
of Alzheimer’s disease. Proc. Natl. Acad. Sci. U.S.A. 100, 11065–
11069.
(13) Committee on Copper in Drinking Water, Board on Environmental
Studies and Toxicology, Commission on Life Sciences, National
Research Council (2000) Copper in Drinking Water, National
Academy Press, Washington, DC.
(14) Deane, R., Sagare, A., Coma, M. (2007) A Novel Role for Copper:
Disruption of LRP-Dependent Brain Abeta Clearance, in Presentation
at the Annual Meeting of the Society for Neuroscience, San Diego,
CA.
(15) Multhaup, G., Schlicksupp, A., Hesse, L., Beher, D., Ruppert, T.,
Masters, C. L., and Beyreuther, K. (1996) The amyloid precursor
protein of Alzheimer’s disease in the reduction of copper(II) to
copper(I). Science 271, 1406–1409.
(16) White, A. R., Multhaup, G., Galatis, D., McKinstry, W. J., Parker,
M. W., Pipkorn, R., Beyreuther, K., Masters, C. L., and Cappa, R.
(2002) Contrasting, species-dependent modulation of copper-mediated
neurotoxicity by the Alzheimer’s disease amyloid precursor protein.
J. Neurosci. 22, 365–376.
(17) Angeletti, B., Waldron, K. J., Freeman, K. B., Bawagan, H., Hussain,
I., Miller, C. C., Lau, K. F., Tennant, M. E., Dennison, C., Robinson,
N. J., and Dingwall, C. (2005) BACE1 cytoplasmic domain interacts
with the copper chaperone for superoxide dismutase-1 and binds
copper. J. Biol. Chem. 280, 17930–17937.
(18) Nelson, T. J., and Alkon, D. L. (2005) Oxidation of cholesterol by
amyloid precursor protein and beta-amyloid peptide. J. Biol. Chem.
280, 7377–7387.
(19) Huang, X., Atwood, C. S., Harthshorn, M. A., Multhaup, G., Goldstein,
L. E., Scarpa, R. C., Cuajungco, M. P., Gray, D. N., Lim, J., Moir,
R. D., Tanzi, R. E., and Bush, A. I. (1999) The A beta peptide of
Alzheimer’s disease directly produces hydrogen peroxide through metal
ion reduction. Biochemistry 38, 7609–7616.
(20) Ma, Q., Li, Y., Du, J., Liu, H., Kanazawa, K., Nemoto, T., Nakanishi,
H., and Zhao, Y. (2006) Copper binding properties of a tau peptide
associated with Alzheimer’s disease studied by CD, NMR and
MALDI-TOF MS. Peptides 27, 841–849.
(21) Sayre, L. M., Perry, G., Harris, P. L., Liu, Y., Schubert, K. A., and
Smith, M. A. (2000) In situ oxidative catalysis by neurofibrillary
tangles and senile plaques in Alzheimer’s disease: a central role for
bound transition metals. J. Neurochem. 74, 270–279.
(22) Squitti, R., Pasqualetti, P., Dal Forno, G., Moffa, F., Assetta, E., Lupoi,
D., Vernieri, F., Rossi, L., Baldassini, M., and Rossini, P. M. (2005)
Excess of serum copper not related to ceruloplasmin in Alzheimer
disease. Neurology 64, 1040–1046.
(23) Squitti, R., Barbati, G., Rossi, L., Ventriglia, M., Dal Forno, G.,
Cesaretti, S., Moffa, F., Caridi, I., Cassetta, E., Pasqualetti, P.,
Calabrese, L., Lupoi, D., and Rossini, P. M. (2006) Excess of
nonceruloplasmin serum copper in AD correlates with MMSE, CSF,
β-amyloid, and h-tau. Neurology 67, 76–82.
(24) Squitti, R., Bressi, F., Pasqualetti, P., Bonomini, C., Ghidoni, R.,
Binetti, G., Cassetta, E., Moffa, F., Ventriglia, M., Vernieri, F., and
Rossini, P. M. (2009) Longitudinal prognostic value of serum “free”
copper in patients with Alzheimer disease. Neurology 72, 50–55.
(25) Miyata, M., and Smith J. D. (1997) Apolipoprotein E, in Stanislaus
Journal of Biochemical ReViews, California State University, Stani-
slaus, CA.
(26) Seshardri, S., Beisner, A., Selhub, J., Jacques, P. F., Rosenberg, I. H.,
D’Agostino, R. B., Wilson, P. W., and Wolf, P. A. (2002) Plasma
homocysteine as a risk factor for dementia and Alzheimer’s disease.
N. Engl. J. Med. 346, 476–483.
(27) Nakano, E., Williamson, M. P., Williams, N. H., and Powers, H. J.
(2004) Copper-mediated LDL oxidation by homocysteine and related
compounds depends largely on copper ligation. Biochim. Biophys. Acta
1688, 33–42.
(28) Phinney, A. L., Drisaldi, B., Schmidt, S. D., Lugowski, S., Coronado,
V. M. A., Cox, D. W., Matthews, P. M., Nixon, R. A., Carlson, G. A.,
St, P., and Westaway, D. (2003) In vivo reduction of amyloid-beta
by a mutant copper transporter. Proc. Assoc. Am. Physicians 100,
14193–14198.
(29) Bayer, T. A., Schafer, S., Simons, A., Kemmling, A., Kamer, T.,
Tepest, R., Eckert, A., Schussel, K., Eikenberg, O., Sturchler-Pierrat,
C., Abramowski, D., Staufenbiel, M., and Multhaup, G. (2003) Dietary
Cu stabilizes brain superoxide dismutase 1 activity and reduces
amyloid Abeta production in APP23 transgenic mice. Proc. Assoc.
Am. Physicians 100, 14187–14192.
(30) Pajonk, F. G., Kessler, H., Supprian, T., Hamzei, P., Bach, D.,
Schwickhardt, J., Hermann, W., Obeid, R., Simons, A., Falkai, P.,
Multhaup, G., and Bayer, T. A. (2005) Cognitive decline correlates
with low plasma concentrations of copper in patients with mild to
moderate Alzheimer’s disease. J. Alzheimer’s Dis. 8, 23–27.
(31) Gaggelli, E., et al. (2006) Copper homeostasis and neurodegenerative
disorders (Alzheimer’s, prion, and Parkinson’s diseases and amyo-
trophic lateral sclerosis). Chem. ReV. 106, 1995.
(32) Brewer, G. J., and Kanzer, S., unpublished studies.
(33) Fox, J. H., Kama, J. A., Lieberman, G., et al. (2007) Mechanisms of
copper ion mediated Huntington’s disease progression. PLoS ONE 2,
e334.
324 Chem. Res. Toxicol., Vol. 23, No. 2, 2010 Brewer
(34) Sigurdesson, E. M., Brown, D. R., Alim, M. A., et al. (2003) Copper
chelation delays the onset of prion disease. J. Biol. Chem. 278, 46199–
46202.
(35) Hottinger, A. F., Fine, E. G., Gurney, M. E., et al. (1997) The copper
chelator D-penicillamine delays onset of disease and extends survival
in a transgenic mouse model of familial amyotrophic lateral sclerosis.
Eur. J. Neurosci. 9, 1548–1551.
(36) Kiaei, M., Bush, A. I., Morrison, B. M., et al. (2004) Genetically
decreased spinal cord copper concentration prolongs life in a transgenic
mouse model of amyotrophic lateral sclerosis. J. Neurosci. 24, 7945–
7950.
(37) Rasia, R. M., Bertoncini, C. W., Marsh, D., et al. (2005) Structural
characterization of copper(II) binding to alpha-synuclein: insights into
the bioinorganic chemistry of Parkinson’s disease. Proc. Natl. Acad.
Sci. U.S.A. 102, 4294–4299.
(38) Morris, M. C., Evans, D. A., Tangney, C. C., et al. (2006) Dietary
copper and high saturated and trans fat intakes associated with
cognitive decline. Arch. Neurol. 63, 1085–1088.
(39) Apostolova, M. D., Bontchev, P. R., Ivanova, B. B., Russell, W. R.,
Mehandjiev, D. R., Beattie, J. H., and Nachev, C. K. (2003) Copper-
homocysteine complexes and potential physiological actions. J. Inorg.
Biochem. 95, 321–333.
(40) Starkebaum, G., and Harlan, J. M. (1986) Endothelial cell injury due
to copper-catalyzed hydrogen peroxide generation from homocysteine.
J. Clin. InVest. 77, 1370–1376.
(41) Hultberg, B., Anderson, A., and Isaksson, A. (1997) The cell-damaging
effects of low amounts of homocysteine and copper ions in human
cell line cultures are caused by oxidative stress. Toxicology 123, 33–
40.
(42) Emsley, A. M., Jeremy, J. Y., Gomes, G. N., Angelini, G. D., and
Plane, F. (1999) Investigation of the inhibitory effects of homocysteine
and copper on nitric oxide-mediated relaxation of rat isolated aorta.
Br. J. Pharmacol. 126, 1034–1040.
(43) Ehrenwald, E., Chisolm, G. M., and Fox, P. L. (1994) Intact human
ceruoplasmin oxidatively modifies low density lipoprotein. J. Clin.
InVest. 93, 1493–1501.
(44) Mukhopadhyay, C. K., Mazumder, B., Lindley, P. F., and Fox, P. L.
(1997) Identification of the prooxidant site of human ceruloplasmin:
a model for oxidative damage by copper bound to protein surfaces.
Proc. Natl. Acad. Sci. U.S.A. 94, 11546–11551.
(45) Fox, P. L., Mazumder, B., Ehrenwald, E., and Mukhopadhyay, C. K.
(2000) Ceruloplasmin and cardiovascular disease. Free Radic. Biol.
Med. 28, 1735–1744.
(46) Lamb, D. J., Avades, T. Y., and Ferns, G. A. (2001) Biphasic
modulation of atherosclerosis induced by graded dietary copper
supplementation in the cholesterol-fed rabbit. Int. J. Exp. Pathol. 82,
287–294.
(47) Cooper, G. J., Phillips, A. R., Choong, S. Y., Leonard, B. L., Crossman,
D. J., Brunton, D. H., Saafi, L., Dissanatyake, A. M., Cowan, B. R.,
Young, A. A., Occleshaw, C. J., Chan, Y. K., Leahy, F. E., Keogh,
G. F., Gamble, G. D., Allen, G. R., Pope, A. J., Boyd, P. D., Poppitt,
S. D., Borg, T. K., Doughty, R. N., and Baker, J. R. (2004)
Regeneration of the heart in diabetes by selective copper chelation.
Diabetes 53, 2501–2508.
(48) Eaton, J. W., and Qian, M. (2002) Interactions of copper with glycated
proteins: possible involvement in the etiology of diabetic neuropathy.
Mol. Cell. Biochem. 234-235, 135–142.
(49) Brewer, G. J., Kanzer, S. H., Zimmerman, E., Hackman, S., and Dick,
R. (2009) Copper abnormalities in Parkinson’s disease, to be submitted
for publication.
(50) Newsome, D., Swartz, M., Leone, N. C., Elston, R. C., and Miller, E.
(1988) Oral zinc in macular degeneration. Arch. Opthamol. 106, 192–
198.
(51) Zhang, Y., Coogan, P., Palmer, J. R., Sham, B. L., and Rosenberg, L.
(2009) Vitamin and mineral use and risk of prostate cancer: the case
control surveillance study. Cancer Causes Control 20, 691–8.
(52) Prasad, A. S. (2008) Clinical, immunological, anti-inflammatory and
antioxidant roles of zinc. Exp. Gerintol. 43, 370–7.
(53) Hu, E., and Song, Y. (2009) Zinc and prostate cancer. Curr. Opin.
Clin. Nutr. Metab. Care 12, 640–5.
(54) Gonzalez, A., Peters, U., Lampe, J. W., and White, E. (2009) Zinc
intake from supplements and diets and prostate cancer. Nutr. Cancer
61, 206–15.
(55) Sullivan, J. L. (1981) Iron and the sex difference in heart disease risk.
Lancet 1, 1293–1294.
(56) Sullivan, J. L. (2003) Are menstruating women protected from heart
disease because of or in spite of estrogen? Relevance to the iron
hypothesis. Am. Heart J. 145, 190–194.
(57) Sullivan, J. L. (2004) Is stored iron safe? J. Lab. Clin. Med. 144, 280–
284.
(58) Gordon, T., Kannel, W. B., Hjortland, M. C., and McNamara, P. M.
(1978) Menopause and coronary heart disease. The Framingham Study.
Ann. Intern. Med. 89, 157–161.
(59) Kannel, W. B., Hjortland, M. C., McNamara, P. M., and Gordon, T.
(1976) Menopause and risk of cardiovascular disease: the Framington
Study. Ann. Intern. Med. 85, 447–452.
(60) Herrington, D. M., Rebourssin, D. M., Brosnihan, K. B., Sharp, P. C.,
Shumaker, S. A., Snyder, T. E., Furberg, C. D., Kowalchuk, G. J.,
Stuckey, T. D., Rogers, W. J., Givens, D. H., and Waters, D. (2000)
Effects of estrogen replacement on the progression of coronary-artery
atherosclerosis. N. Engl. J. Med. 343, 522–529.
(61) Hulley, S., Grady, D., Bush, T., Furberg, C., Herrington, D., Riggs,
B., and Vittinghoff, E. (1998) Randomized trial of estrogen plus
progestin for women. Heart and Estrogen/progestin Replacement Study
(HERS) Research Group. JAMA 280, 605–613.
(62) You, S. A., and Wang, Q. (2005) Ferritin in atherosclerosis. Clin. Chim.
Acta 357, 1–16.
(63) Sullivan, J. L. (2007) Macrophage iron, hepcidin, and atherosclerotic
plaque stability. Exp. Biol. Med. 232, 1014–1020.
(64) Ong, W. Y., and Halliwell, B. (2004) Iron, atherosclerosis, and
neurodegeneration: a key role for cholesterol in promoting iron-
dependent oxidative damage? Ann. N.Y. Acad. Sci. 1012, 51–64.
(65) Zecca, L., Youdim, M. B., Riederer, P., Connor, J. R., and Crichton,
R. R. (2004) Iron, brain ageing and neurodegenerative disorders. Nat.
ReV. Neurosci. 5, 863–873.
(66) Moalem, S., Percy, M. E., Andrews, D. F., Kruck, T. P., Wong, S.,
Dalton, A. J., Mehta, P., Fedor, B., and Warren, A. C. (2000) Are
hereditary hemochromatosis mutations involved in Alzheimer disease?
Ann. J. Med. Genet. 93, 58–66.
(67) Zambenedetti, P., De Bellis, G., Biunno, I., Musicco, M., and Zatta,
P. (2003) Transferrin C2 variant does confer a risk for Alzheimer’s
disease in Caucasians. J. Alzheimers Dis. 5, 423–427.
(68) Van Landeghem, G. F., Sikstrom, C., Beckman, L. E., Adolfsson, R.,
and Beckman, L. (1998) Transferrin C2 metal binding and Alzheimer’s
disease. Neuroreport 9, 177–179.
(69) Namekata, K., Imagawa, M., Terashi, A., Ohta, S., Oyama, F., and
Ihura, Y. (1997) Association of transferrin C2 allele with late-onset
Alzheimer’s disease. Hum. Genet. 101, 126–129.
(70) Robson, K. J., Lehmann, D. J., Wimhurst, V. L., Livesey, K. J.,
Combrinck, M., Merryweather-Clarke, A. T., Warden, D. R., and
Smith, A. D. (2004) Synergy between the C2 allele of transferrin and
the C282Y allele of the haemochromatosis gene (HFE) as risk factors
for developing Alzheimer’s disease. J. Med. Genet. 41, 261–265.
(71) Crapper McLachlan, D. R., Dalton, A. J., Kruck, T. P., Bell, M. Y.,
Smith, W. L., Kalow, W., and Andrews, D. F. (1991) Intramuscular
desferrioxamine in patients with Alzheimer’s disease. Lancet 337,
1304–1308.
(72) Harman, D. (1956) Aging: a theory based on free radical and radiation
chemistry. J. Gerontol. 11, 298–300.
(73) Harman, D. (1969) Prolongation of life: role of free radical reactions
in aging. J. Am. Geriatr. Soc. 17, 721–735.
(74) Butterfield, D. A., and Lauderback, C. M. (2002) Lipid peroxidation
and protein oxidation in Alzheimer’s disease brain: potential causes
and consequences involving amyloid beta-peptide-associated free
radical oxidative stress. Free Radical Biol. Med. 32, 1050–1060.
(75) Butterfield, D. A. (2004) Proteomics: a new approach to investigate
oxidative stress in Alzheimer’s disease brain. Brain Res. 1000, 1–7.
(76) Eaton, J. W., and Qian, M. (2002) Molecular bases of cellular iron
toxicity. Free Radical Biol. Med. 32, 833–840.
(77) Schipper, H. M. (2004) Brain iron deposition and the free radical-
mitochondrial theory of ageing. Ageing Res. ReV.3, 265–301.
(78) Massie, H. R., Aiello, V. R., and Williams, T. R. (1993) Inhibition of
iron absorption prolongs the life span of Drosophila.Mech. Ageing
DeV.67, 227–237.
(79) Sohal, R. S., Farmer, K. J., Allen, R. G., and Ragland, S. S. (1984)
Effects of diethyldithiocarbamate on life span, metabolic rate, super-
oxide dismutase catalase, inorganic peroxides and glutathione in the
adult male housefly, Musca domestica.Mech. Ageing DeV.24, 175–
183.
(80) Mainous, A. G., Gill, J. M., and Carek, P. J. (2004) Elevated serum
transferrin saturation and mortality. Ann. Fam. Med. 2, 133–138.
(81) Mainous, A. G., Wells, B., Carek, P. J., Gill, J. M., and Geesey, M. E.
(2004) The mortality risk of elevated serum transferrin saturation and
consumption of dietary iron. Ann. Fam. Med. 2, 139–144.
(82) Srikumar, T. S., Johansson, G. K., Ockerman, P. A., Gustafsson, J. A.,
and Akesson, B. (1992) Trace element status in healthy subjects
switching from a mixed to a lactovegetarian diet for 12 mo. Am. J.
Clin. Nutr. 55, 1–6.
(83) Brewer, G. J., Yuzbasiyan-Gurkan, V., Dick, R., Wang, Y., and
Johnson, V. (1993) Does a vegetarian diet control Wilson’s disease?
J. Am. Coll. Nutr. 12 (5), 527–30.
(84) Liebman, B. (2009) The real cost of red meat. Nutr. Action Health
Lett., June, 36,3-7.
(85) Sinha, R., Cuss, A. J., Graubard, B. I., Leitzmann, M. F., and Schatzkin,
A. (2009) Meat intake and mortality: a prospective study of over half
a million people. Arch. Intern. Med. 169, 562–571.
ReView Chem. Res. Toxicol., Vol. 23, No. 2, 2010 325
(86) Brewer, G. J., Dick, R. D., Johnson, V. D., Branberg, J. A., Kluin,
K. J., and Fink, J. K. (1998) The treatment of Wilson’s disease with
zinc: XV Long term follow-up studies. J. Lab. Clin. Med. 132, 264–
278.
(87) Brewer, G. J., Dick, R., Zeng, C., and Hoa, G. (2006) The use of
tetrathiomolybdate in treating fibrotic, inflammatory, and autoimmune
diseases, including non-obese diabetic mouse model. J. Inorg. Bio-
chem. 100, 927–930.
(88) Hou, G., Dick, R., Zeng, C., and Brewer, G. J. (2006) Comparison of
lowering copper levels with tetrathiomolybdate and zinc on mouse
tumor and doxorubicin models. Transl. Res. 148, 309–314.
(89) Waldman, M., and Lamb, M. (2005) Dying for a Hamburger, Thomas
Dunne Books, St. Martin’s Press, New York, NY.
TX900338D
326 Chem. Res. Toxicol., Vol. 23, No. 2, 2010 Brewer
... The widespread industrial utilization, coupled with inadequate disposal practices for industrial and mining effluents, has resulted in the release of copper ions, Cu(II), into the environment. Elevated concentrations of Cu(II) in drinking water have been linked to various adverse health effects, including neuropsychiatric disorders such as schizophrenia and Alzheimer's disease, age-related illnesses, and Indian childhood cirrhosis (Brewer 2010;Puentes-Díaz et al. 2023). Furthermore, high Cu(II) levels in aquatic ecosystems pose a significant threat to aquatic life. ...
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This study investigates the adsorption of pollutants with different chemical structures; organic Naphtol Green B (NGB) dye and copper on a nanocomposite material with a hexagonal structure of the SBA-15 type. This research is divided into two main parts: the first carries out the synthesis of SBA-15 (Santa Barbra Amourphous) and its derivatives phases functionalized by 3-aminopropyl-triethoxylane (APTES) and calcined at 823 K. The second part presents the influence of the adsorption conditions on the adsorption efficiency of NGB dye and copper. High-resolution X-ray diffractogram (XRD) showed three distinct peaks characteristic of highly ordered mesoporous material. Nitrogen adsorption–desorption isotherm of SBA-15 at 77 K° is type IV typical of mesoporous materials. In addition, Fourier transform infrared spectroscopy (FT-IR) was also used in the characterization before and after the adsorption of the selected pollutants. At optimal conditions of pH 5.2, initial concentration of 50 mg/L, adsorbent dosage of 20 mg, and at adsorption time of 90 min the maximum removal of pollutants reached 76% and the adsorption capacity was 227.25 mg/g for NGB dye and 221.006 mg/g for copper. Furthermore, the adsorption kinetics followed the pseudo-second-order model, indicating that chemisorption was the dominant mechanism and the Sips isotherm model best described the adsorption data. Our research demonstrates that the SBA-15 material after modification is an effective adsorbent for removing effluents regardless of their different chemical structure (organic and inorganic).
... There are several studies documenting abnormalities in iron metabolism, as well as the accumulation of this element in the liver and in the brains of patients with WD [30][31][32][33][34][35]. Impairment of iron metabolism results mainly from disturbances in the synthesis/enzymatic function of ceruloplasmin (CPN), which, due to disturbances in copper metabolism, is not transformed into a mature, fully active holoCPN molecule, the presence of which is fundamentally important for proper iron metabolism. ...
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Wilson’s disease (WD) is inherited in an autosomal recessive manner and is caused by pathogenic variants of the ATP7B gene, which are responsible for impaired copper transport in the cell, inhibition of copper binding to apoceruloplasmin, and biliary excretion. This leads to the accumulation of copper in the tissues. Copper accumulation in the CNS leads to the neurological and psychiatric symptoms of WD. Abnormalities of copper metabolism in WD are associated with impaired iron metabolism. Both of these elements are redox active and may contribute to neuropathology. It has long been assumed that among parenchymal cells, astrocytes have the greatest impact on copper and iron homeostasis in the brain. Capillary endothelial cells are separated from the neuropil by astrocyte terminal legs, putting astrocytes in an ideal position to regulate the transport of iron and copper to other brain cells and protect them if metals breach the blood–brain barrier. Astrocytes are responsible for, among other things, maintaining extracellular ion homeostasis, modulating synaptic transmission and plasticity, obtaining metabolites, and protecting the brain against oxidative stress and toxins. However, excess copper and/or iron causes an increase in the number of astrocytes and their morphological changes observed in neuropathological studies, as well as a loss of the copper/iron storage function leading to macromolecule peroxidation and neuronal loss through apoptosis, autophagy, or cuproptosis/ferroptosis. The molecular mechanisms explaining the possible role of glia in copper- and iron-induced neurodegeneration in WD are largely understood from studies of neuropathology in Parkinson’s disease and Alzheimer’s disease. Understanding the mechanisms of glial involvement in neuroprotection/neurotoxicity is important for explaining the pathomechanisms of neuronal death in WD and, in the future, perhaps for developing more effective diagnostic/treatment methods.
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Seven novel polycyclic pyrazoline and pyrazole sensors were synthesised and screened for useful photophysical properties with pyrazoline 2 and pyrazole 7, displaying an Fe³⁺ “turn-off” response in aqueous environments with Fe³⁺ limits of detection (LoD) of 2.12 μM and 3.41 μM, respectively. Both 2 and 7 sensors functioned in aqueous environments with real-world examples of Fe³⁺ detection in tap water and mineral water samples. 2 and 7 are suitable for the detection of Fe³⁺ at concentrations below the maximum iron limits for drinking water set by the Environmental Protection Agency (EPA) and European Union (EU).
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Alzheimer's disease (AD) is the major cause of irreversible dementia in the elderly population worldwide and one of the major causes of the decrease in the quality of life. Efficient...
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Mining-associated activities result in iron pollution exceeding the acceptable limit of 0.3 mg L− 1 and are rampant in estuarine soil and water bodies that harbor halophilic microorganisms. Biotechnologies are underway to unveil the concentrations and recover the metals that skip existing physico-chemical methods. Concerning this, the present study describes for the first time the development of a bio-adsorption batch system using dried cells of Haloferax alexandrinus GUSF-1 for Fe (II) from saline water under microaerophilic conditions. A maximum of 99.5% Fe (II) was adsorbed at pH 6.0, 30 ºC in 3 h with 92% efficiency over three adsorption-desorption cycles with saturation and pseudo-second-order kinetics and heterogeneity of Freundlich model having KF of 1.38 mg g− 1 with the n value of 0.96. Adsorbed Fe (II) by the cells was detected by scanning electron microscopy. The involvement of the carboxyl, amino, hydroxyl, and phosphate groups of the cells in interaction with the metal ions was detected by infrared spectroscopy. Conclusively, the study is the first report of whole dried cells mediated metal adsorption by the haloarcheon Haloferax alexandrinus GUSF-1 which acts as promising candidate for metal clean-up strategy and bioremediation in hypersaline ecosystems.
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Efficient water treatment ideally combines ion exchange for the removal of hardness elements and toxic trace metals as well as ultrafiltration for the removal of particulate matter. Although promising for adsorption, many high‐surface‐area polymer materials cannot be easily processed into freestanding membranes or packed bed columns, due to poor solution processability and high back pressures, respectively. The preparation of hybrid membranes comprising sulfonated hypercrosslinked polymers entrapped in nanocellulose papers is described. The hybrid membranes are effective for simultaneous ultrafiltration and ion exchange. Increasing the polymer loading of the hybrid membrane produces synergy by increasing the permeance of the membranes while enhancing the ion adsorption capacity to values exceeding those of bulk hypercrosslinked polymers. The maximum ion adsorption capacity for copper is determined to be ≈100 mg g⁻¹ outperforming that of pure polymer (71 mg g⁻¹) and commercially available ion exchange resins. Competitive adsorption is tested in samples containing water hardness elements and trace toxic metal ions showing high ion‐exchange capacities. Even when fully loaded with water hardness elements, Ba²⁺ and Sr²⁺ are still removed from solution.
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Essential transition metals have key roles in oxygen transport, neurotransmitter synthesis, nucleic acid repair, cellular structure maintenance and stability, oxidative phosphorylation, and metabolism. The balance between metal deficiency and excess is typically ensured by several extracellular and intracellular mechanisms involved in uptake, distribution, and excretion. However, provoked by either intrinsic or extrinsic factors, excess iron, zinc, copper, or manganese can lead to cellular damage upon chronic or acute exposure, frequently attributed to oxidative stress. Intracellularly, mitochondria are the organelles that require the tightest control concerning reactive oxygen species production, which inevitably leaves them to be one of the most vulnerable targets of metal toxicity. Current therapies to counteract metal overload are focused on chelators, which often cause secondary effects decreasing patients’ quality of life. New therapeutic options based on synthetic or natural antioxidants have proven positive effects against metal intoxication. In this review, we briefly address the cellular metabolism of transition metals, consequences of their overload, and current therapies, followed by their potential role in inducing oxidative stress and remedies thereof.
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Context.— Observational studies have found lower rates of coronary heart disease (CHD) in postmenopausal women who take estrogen than in women who do not, but this potential benefit has not been confirmed in clinical trials.Objective.— To determine if estrogen plus progestin therapy alters the risk for CHD events in postmenopausal women with established coronary disease.Design.— Randomized, blinded, placebo-controlled secondary prevention trial.Setting.— Outpatient and community settings at 20 US clinical centers.Participants.— A total of 2763 women with coronary disease, younger than 80 years, and postmenopausal with an intact uterus. Mean age was 66.7 years.Intervention.— Either 0.625 mg of conjugated equine estrogens plus 2.5 mg of medroxyprogesterone acetate in 1 tablet daily (n=1380) or a placebo of identical appearance (n=1383). Follow-up averaged 4.1 years; 82% of those assigned to hormone treatment were taking it at the end of 1 year, and 75% at the end of 3 years.Main Outcome Measures.— The primary outcome was the occurrence of nonfatal myocardial infarction (MI) or CHD death. Secondary cardiovascular outcomes included coronary revascularization, unstable angina, congestive heart failure, resuscitated cardiac arrest, stroke or transient ischemic attack, and peripheral arterial disease. All-cause mortality was also considered.Results.— Overall, there were no significant differences between groups in the primary outcome or in any of the secondary cardiovascular outcomes: 172 women in the hormone group and 176 women in the placebo group had MI or CHD death (relative hazard [RH], 0.99; 95% confidence interval [CI], 0.80-1.22). The lack of an overall effect occurred despite a net 11% lower low-density lipoprotein cholesterol level and 10% higher high-density lipoprotein cholesterol level in the hormone group compared with the placebo group (each P<.001). Within the overall null effect, there was a statistically significant time trend, with more CHD events in the hormone group than in the placebo group in year 1 and fewer in years 4 and 5. More women in the hormone group than in the placebo group experienced venous thromboembolic events (34 vs 12; RH, 2.89; 95% CI, 1.50-5.58) and gallbladder disease (84 vs 62; RH, 1.38; 95% CI, 1.00-1.92). There were no significant differences in several other end points for which power was limited, including fracture, cancer, and total mortality (131 vs 123 deaths; RH, 1.08; 95% CI, 0.84-1.38).Conclusions.— During an average follow-up of 4.1 years, treatment with oral conjugated equine estrogen plus medroxyprogesterone acetate did not reduce the overall rate of CHD events in postmenopausal women with established coronary disease. The treatment did increase the rate of thromboembolic events and gallbladder disease. Based on the finding of no overall cardiovascular benefit and a pattern of early increase in risk of CHD events, we do not recommend starting this treatment for the purpose of secondary prevention of CHD. However, given the favorable pattern of CHD events after several years of therapy, it could be appropriate for women already receiving this treatment to continue. Figures in this Article MANY OBSERVATIONAL studies have found lower rates of coronary heart disease (CHD) in women who take postmenopausal estrogen than in women not receiving this therapy.1- 5 This association has been reported to be especially strong for secondary prevention in women with CHD, with hormone users having 35% to 80% fewer recurrent events than nonusers.6- 12 If this association is causal, estrogen therapy could be an important method for preventing CHD in postmenopausal women. However, the observed association between estrogen therapy and reduced CHD risk might be attributable to selection bias if women who choose to take hormones are healthier and have a more favorable CHD profile than those who do not.13- 15 Observational studies cannot resolve this uncertainty. Only a randomized trial can establish the efficacy and safety of postmenopausal hormone therapy for preventing CHD. The Heart and Estrogen/progestin Replacement Study (HERS) was a randomized, double-blind, placebo-controlled trial of daily use of conjugated equine estrogens plus medroxyprogesterone acetate (progestin) on the combined rate of nonfatal myocardial infarction (MI) and CHD death among postmenopausal women with coronary disease. We enrolled women with established coronary disease because their high risk for CHD events and the strong reported association between hormone use and risk of these events make this an important and efficient study population in which to evaluate the effect of hormone therapy.
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Huntington's disease (HD) is caused by a dominant polyglutamine expansion within the N-terminus of huntingtin protein and results in oxidative stress, energetic insufficiency and striatal degeneration. Copper and iron are increased in the striata of HD patients, but the role of these metals in HD pathogenesis is unknown. We found, using inductively-coupled-plasma mass spectroscopy, that elevations of copper and iron found in human HD brain are reiterated in the brains of affected HD transgenic mice. Increased brain copper correlated with decreased levels of the copper export protein, amyloid precursor protein. We hypothesized that increased amounts of copper bound to low affinity sites could contribute to pro-oxidant activities and neurodegeneration. We focused on two proteins: huntingtin, because of its centrality to HD, and lactate dehydrogenase (LDH), because of its documented sensitivity to copper, necessity for normoxic brain energy metabolism and evidence for altered lactate metabolism in HD brain. The first 171 amino acids of wild-type huntingtin, and its glutamine expanded mutant form, interacted with copper, but not iron. N171 reduced Cu(2+)in vitro in a 1:1 copper:protein stoichiometry indicating that this fragment is very redox active. Further, copper promoted and metal chelation inhibited aggregation of cell-free huntingtin. We found decreased LDH activity, but not protein, and increased lactate levels in HD transgenic mouse brain. The LDH inhibitor oxamate resulted in neurodegeneration when delivered intra-striatially to healthy mice, indicating that LDH inhibition is relevant to neurodegeneration in HD. Our findings support a role of pro-oxidant copper-protein interactions in HD progression and offer a novel target for pharmacotherapeutics.
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The relation of menopause to cardiovascular disease incidence was examined in women less than 55 years old from the cohort of 2873 women in the initial Framingham examination. Although the number of person-years of experience during the 20 years of observation was nearly the same for premenopausal and postmenopausal status, there were only 20 cardiovascular events among the premenopausal women in this age group whereas 70 events occurred among the postmenopausal women of the same age. In each specific age group studied incidence rates were lower in premenopausal than postmenopausal women. This was also true for coronary heart disease. Contrast for "hard" diagnoses of cardiovascular disease (excluding diagnoses of angina pectoris and intermittent claudication) was in the same direction. Although cholesterol and hemoglobin did rise somewhat more steeply in women undergoing the menopause, this greater incidence of cardiovascular disease in postmenopausal women could not be explained by the influence of the menopause on the usual cardiovascular risk factors.
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Amyloid β-peptide (Aβ) is heavily deposited in the brains of Alzheimer’s disease (AD) patients, and free radical oxidative stress, particularly of neuronal lipids and proteins, is extensive. Recent research suggests that these two observations may be linked by Aβ-induced oxidative stress in AD brain. This review summarizes current knowledge on phospholipid peroxidation and protein oxidation in AD brain, one potential cause of this oxidative stress, and consequences of Aβ-induced lipid peroxidation and protein oxidation in AD brain.
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BACKGROUND A large proportion of US adults have elevated transferrin saturation, an indicator of a predisposition for iron overload. The purpose of this study was to evaluate the relationship between elevated serum transferrin saturation and mortality. METHODS This cohort study was conducted using data from the First Health and Nutrition Examination Survey I (1971–1974) (NHANES I) merged with the NHANES I Epidemiologic Followup Study (1992) (N = 10,714). We used SUDAAN and appropriate weights to make population estimates for the adult US population (aged 25 to 74 years at baseline). All-cause mortality was evaluated in relation to serum transferrin saturation of greater than 45%, greater than 50%, greater than 55%, and greater than 60% using Cox proportional hazards regression. RESULTS In a Cox proportional hazards model controlling for potential confounders, including comorbid diseases, smoking, and cholesterol, all-cause mortality is significantly greater for persons with a serum transferrin saturation of more than 55%, compared with those with saturations below this cutoff (hazards ratio [HR] =1.60, 95% confidence interval [CI], 1.17–2.21). No one who died had hemochromatosis as any of the 20 listed causes of death. Many of the underlying causes of death for persons with serum transferrin saturation levels of more than 55% are common causes of death in the general population, although these persons were more likely to have died of cirrhosis and diabetes, a finding consistent with iron overload. CONCLUSIONS In this nationally representative cohort of adults, those with elevated serum transferrin saturation, more than 2% of the adult US population, were at increased risk for all-cause mortality.
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BACKGROUND Recent data shows an increased mortality risk associated with elevated transferrin saturation. Because ingestion of dietary iron may contribute to iron overload in persons with elevated transferrin saturation, we investigated the relationship between elevated transferrin saturation, ingestion of dietary iron and red meat, and mortality. METHODS This 12-year cohort study used data from the second National Health and Nutrition Examination Survey 1976–1980 (NHANES II) and the NHANES II Mortality Study 1992. Population estimates were based on 9,229 persons aged 35 to 70 years at baseline. A Cox proportional hazards analysis was performed based on levels of transferrin saturation, intake of dietary iron, and intake of red meat. The analysis was conducted while controlling for demographics, severity of illness, body mass index, and smoking status. RESULTS Unadjusted analyses indicated that those who had a high transferrin saturation and reported high dietary iron or red meat consumption had an increased mortality risk. The adjusted survival analysis indicated that persons with elevated transferrin saturation who reported high dietary iron intake had a hazard ratio for death of 2.90 (95% confidence interval [CI], 1.39–6.04) compared with those with normal transferrin saturation levels and reported low dietary iron intake. Persons who had a high transferrin saturation and reported high red meat consumption also had an increased hazard ratio for death (2.26; 95% CI, 1.45–3.52) compared with those who had normal transferrin saturation and reported low red meat consumption. CONCLUSIONS Ingestion of large quantities of dietary iron and red meat in persons with high transferrin saturation is associated with an increase in mortality. Simple dietary restrictions may reduce the mortality risk associated with high transferrin saturation.
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