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Mercury Toxicity and Antioxidants: Part I: Role of Glutathione and alpha-Lipoic Acid in the Treatment of Mercury Toxicity

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Mercury exposure is the second-most common cause of toxic metal poisoning. Public health concern over mercury exposure, due to contamination of fish with methylmercury and the elemental mercury content of dental amalgams, has long been a topic of political and medical debate. Although the toxicology of mercury is complex, there is evidence for antioxidant protection in the prevention of neurological and renal damage caused by mercury toxicity. Alpha-lipoic acid, a coenzyme of pyruvate and alpha-ketoglutarate dehydrogenase, has been used in Germany as an antioxidant and approved treatment for diabetic polyneuropathy for 40 years. Research has attempted to identify the role of antioxidants, glutathione and alpha-lipoic acid specifically, in both mitigation of heavy metal toxicity and direct chelation of heavy metals. This review of the literature will assess the role of glutathione and alpha-lipoic acid in the treatment of mercury toxicity.
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Page 456 Alternative Medicine Review
Volume 7, Number 6 2002
Mercury Toxicity Review
Copyright©2002 Thorne Research, Inc. All Rights Reserved. No Reprint Without Written Permission
Lyn Patrick, ND – 1984 graduate, Bastyr University;
associate editor, Alternative Medicine Review; private
practice, Tucson, Arizona, 1984-2002.
Correspondence address: 21415 Hwy 140, Hesperus, CO
81326 Email: lpatrick@frontier.net
Mercury Toxicity and Antioxidants:
Part I: Role of Glutathione and alpha-Lipoic
Acid in the Treatment of Mercury Toxicity
Lyn Patrick, ND
Abstract
Mercury exposure is the second-most common
cause of toxic metal poisoning. Public health
concern over mercury exposure, due to
contamination of fish with methylmercury and
the elemental mercury content of dental
amalgams, has long been a topic of political
and medical debate. Although the toxicology
of mercury is complex, there is evidence for
antioxidant protection in the prevention of
neurological and renal damage caused by
mercury toxicity. Alpha-lipoic acid, a coenzyme
of pyruvate and alpha-ketoglutarate
dehydrogenase, has been used in Germany as
an antioxidant and approved treatment for
diabetic polyneuropathy for 40 years. Research
has attempted to identify the role of
antioxidants, glutathione and alpha-lipoic acid
specifically, in both mitigation of heavy metal
toxicity and direct chelation of heavy metals.
This review of the literature will assess the role
of glutathione and alpha-lipoic acid in the
treatment of mercury toxicity.
(Altern Med Rev 2002;7(6):456-471)
Mercury: Sources of Exposure
According to the Agency for Toxic
Substances and Disease Registry (ATSDR) of the
U.S. Department of Health and Human Services,
mercury is listed as the third-most frequently found
(lead and arsenic are first and second), and the
most toxic substance in the United States.
1
This
figure originates from the U.S. Government’s
Priority List of Hazardous Substances. This list
includes, in order of priority, substances that have
been found at hazardous waste sites on the
National Priorities List (Superfund sites) that “pose
the most significant potential threat to human
health due to their known or suspected toxicity
and the frequency of exposure.” Of 1,467
hazardous waste sites listed on the National
Priorities List in 1998, toxic levels of mercury
were identified in 714. Mercury toxicity is also
considered the second-most common cause of
acute heavy metal poisoning, with 3,596 cases
reported in 1997 by the American Association of
Poison Control Centers.
2
Annual worldwide emissions of mercury
into the atmosphere have been estimated at 2,200
metric tons.
3
One-third of these emissions are es-
timated to originate from natural sources (volca-
nic eruptions and decay of mercury-containing
sediment) and two-thirds from man-made sources.
Twenty-five percent of total worldwide emissions
come from fossil fuel combustion. In the United
States, 26 percent (64.7 tons/year) of atmospheric
mercury emissions come from medical waste
incineration, such as cremation.
4
There are currently 1,782 advisories (one
per body of water) issued by the U.S. Environ-
mental Protection Agency (EPA) in 41 states in
the United States restricting the consumption of
any locally caught fish or shellfish due to their
mercury content. Sixteen states have issued state-
wide or statewide-coastal advisories recommend-
ing restricting the consumption of fish caught in
the state or along the coastline due to methyl-
mercury contamination.
4
The Environmental
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Alternative Medicine Review
Volume 7, Number 6 2002 Page 457
Review Mercury Toxicity
Working Group, in a presentation to the Food
Advisory Committee of the U.S. Food and Drug
Adminstration (FDA), recently presented data
warning of the consequences for fetuses of women
who follow the current FDAs fish consumption
advisory and eat 12 ounces of “safe” fish per week.
The Environmental Working Group estimates that
more than 25 percent of children in utero in the
United States would be exposed to levels of mer-
cury above the EPA safe reference dose (0.1 µg
methylmercury/kg body weight/day) for at least
30 days during gestation and would have an in-
creased risk for neurological damage.
5
The ATSDR considers anyone who lives
in close proximity to a former mercury mining site,
recycling facility, municipal or medical incinera-
tor, or coal-fired electric generating plant to be at
risk for mercury toxicity. Anyone who routinely
consumes contaminated fish, subsistence hunters
who consume meat or organ tissues of marine
mammals or feral wildlife, individuals with a
“large number” of dental amalgams, pregnant or
nursing women (and their developing fetuses and
breast-fed babies), those who use consumer prod-
ucts containing mercury (skin-lightening creams
or antiseptic facial products, mercury-containing
diuretics or laxatives, and teething powders), or
those living or working in buildings painted with
mercury-containing latex paint are also considered
at significant risk. Mercury-containing latex paint
was removed from paint manufacturing in 1991
but may still be available in the reserve invento-
ries of contractors and warehouses.
4
Mercury is found in the environment in
three basic states: elemental mercury or mercury
vapor, inorganic mercury, and organic mercury
(ethyl-, methyl-, alkyl-, or phenylmercury). Each
form has an individual toxicological profile and
metabolic fate. The most frequent source of mer-
cury exposure is open to debate. On an individual
exposure basis, the estimated intake and retention
of elemental mercury vapor (from dental amal-
gams and atmospheric pollution) in non-occupa-
tionally exposed individuals has a much broader
range (3.9-21.0 µg/day) than either inorganic (4.3
µg/day) or methylmercury (1-6 µg/day) exposure.
6
Elemental Mercury
Elemental mercury, found in thermo-
meters, thermostats, dental amalgams, and mer-
cury added to latex paint, eventually enters a va-
porized state. Eighty percent of inhaled elemen-
tary mercury vapor is absorbed and can cross the
blood-brain barrier or reach the placenta.
2
Mer-
cury vapor in the gastrointestinal tract is converted
to mercuric sulfide and excreted in the feces.
6
Mer-
cury vapor in the kidneys, however, the main re-
pository for elemental mercury, is carried to all
parts of the central nervous system as a lipid-
soluble gas. Mercury vapor can also be oxidized
to inorganic mercury by catalase and can attach
to the thiol groups in most proteins – enzymes,
glutathione, or almost any structural protein.
7
Elemental mercury can also be methylated by
microorganisms in soil and water and potentially
the human gastrointestinal tract,
8
where it can then
be transformed into organic methylmercury, the
form found in fish, fungicides, and pesticides. El-
emental mercury and its metabolites have the toxic
effect of denaturing biological proteins, inhibit-
ing enzymes, and interrupting membrane trans-
port and the uptake and release of neurotransmit-
ters.
7
Chronic exposure most commonly manifests
as a triad of increased excitability and irritability,
tremors, and gingivitis.
2
Less commonly, chronic
exposure causes central and peripheral nervous
system damage, manifesting as a characteristic fine
tremor of the extremities and facial muscles, emo-
tional lability, and irritability. Rarely, significant
exposure can cause acrodynia or “pink disease,”
involving a pink rash on the extremities, pruritis,
paresthesias, and pain.
9
Inorganic Mercury
Inorganic mercury (mercury salts) is
found in cosmetic products, laxatives, teething
powders, diuretics, and antiseptics.
2
Inorganic
mercury can be formed from the metabolism of
elemental mercury vapor or methylmercury.
7
Al-
though inorganic mercury does not normally reach
the placenta or cross the blood-brain barrier, it has
been found in the neonatal brain due to the ab-
sence of a fully formed blood-brain barrier.
6
In-
organic mercury is complexed with glutathione in
Page 458 Alternative Medicine Review
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Mercury Toxicity Review
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the liver and secreted in the bile as a cysteine-
mercury or glutathione-mercury complex. Chronic
exposure to inorganic mercury salts primarily af-
fects the renal cortex
10
and may manifest as renal
failure (dysuria, proteinuria, hematuria, oliguria,
and uremia) or gastrointestinal problems (colitis,
gingivitis, stomatitis, and excessive salivation).
Irritability and occasionally acrodynia can occur.
2
Organic Mercury
Considered the most toxic and most fre-
quent form of mercury exposure, organic mercury
is found in fish, poultry that has been fed fishmeal,
pesticides, fungicides, insecticides, and thimero-
sal-containing vaccines. Thimerosal, which is
49.6-percent ethylmercury (a form of organic
mercury), has been used as a preservative in vac-
cinations since the 1930s. It is currently mixed
with DTaP, HIB, and hepatitis B vaccines or is
used in the manufacturing process for vaccines,
with resultant trace amounts being present in the
final product. Based on existing Centers for Dis-
ease Control (CDC) recommendations for vacci-
nations, a typical six-month-old child, if receiv-
ing all thimerosal-containing vaccines, could
potentially be injected with as much as 187.5-200
µg of methylmercury; the equivalent of more than
1.0 µg per day. This amount exceeds the refer-
ence limits for exposure to mercury set by the EPA
of 0.1 µg/kg/day.
11
In the United States, at the
FDAs request, all vaccines are currently being
produced as thimerosal-free or thimerosal-reduced
(> 95-percent reduction) vaccines. Thimerosal-
preserved vaccines are still available and used in
clinical practice.
Methylmercury is almost completely ab-
sorbed (95-100 percent) in the human gastro-
intestinal tract,
2,7
90 percent of which is eventu-
ally eliminated through the feces. Methylmercury
is present in the body as a water-soluble complex,
mainly with the sulfur atom of thiol ligands,
7
and
crosses the blood-brain barrier complexed with L-
cysteine in a molecule resembling methionine.
Methylmercury is absorbed into the placenta and
stored in the fetal brain in concentrations that ex-
ceed maternal blood levels.
12
After being released
from cells in a complex with reduced glutathione,
methylmercury is degraded in the bile duct to an
L-cysteine complex. Only 10 percent of methyl-
mercury is eliminated through the kidneys. The
rest either undergoes enterohepatic recycling or
demethylation by microflora in the intestine and
immune system and eventual elimination through
the feces.
Most methyl mercury in animal exposure
studies is degraded to, and eliminated as, inorganic
mercury at the rate of one percent per day.
7
At least
one study has demonstrated the capacity of two
common forms of gastrointestinal yeast to con-
vert inorganic mercury to methylmercury.
8
Demethylation by intestinal microflora is a cru-
cial step in the elimination of methylmercury from
the body, but research has not yet identified the
mechanisms or the microbes responsible for this
detoxification system.
7
Enterohepatic reabsorption
is also a significant event in the metabolism of
methylmercury; more than 70 percent is re-
absorbed from the gut and returned to the liver.
7,13
Inorganic mercury has been found as the
major form of mercury in brain tissue in humans
fatally exposed to methylmercury.
14
The conver-
sion of methylmercury to inorganic mercury is
thought to take place in phagocytic cells in the
liver or in the astroglial cells of the brain.
7
The majority of toxicity due to methyl-
mercury exposure involves the central nervous
system. Methylmercury can cause demyelination,
autonomic dysfunction, sensory nerve conduction
delay, abnormal neuronal migration, and abnor-
mal central nervous system cell division. Chronic
toxicity symptoms include paresthesia, peripheral
neuropathy, cerebellar ataxia, akathisia, spastic-
ity, memory loss, dementia, constricted vision,
dysarthria, impaired hearing, smell and taste, trem-
ors, and depression.
2,7
Methylmercury exposure also appears to
increase risk for cardiovascular disease. In a long-
term prospective study, both intake of nonfatty
freshwater fish and hair mercury content demon-
strated a statistically significant correlation with
increased risk for acute myocardial infarction.
15
Men with the highest hair mercury had a 2.9-fold
increased risk for cardiovascular death. An exami-
nation of the same cohort found a significant cor-
relation between hair mercury and increased risk
Alternative Medicine Review
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for progression of carotid atherosclerosis.
16
Prenatal exposure to methylmercury has been cor-
related with significant blood pressure elevations
in seven-year-old children as a result of maternal
fish intake.
17
Table 1. Mercury Species – Sources, Routes of Absorption, Distribution, and
Excretion
18
Sources
Absorption
Distribution
Metabolism
Excretion
Cause of
Toxicity
Methylmercury
Fish, poultry,
pesticides
95-100 percent in
intestinal tract; 100
percent of inhaled
vapor
Lipophilic, distributed
throughout body;
readily crosses blood-
brain barrier and
placental barrier;
accumulates in brain,
kidney
Cysteine complex
necessary for
intracellular
absorption; slowly
demethylated to
inorganic mercury in
brain by tissue
macrophages, fetal
liver, and free radicals
90 percent in
bile,feces; 10 percent
in urine
Demethylation to
inorganic (divalent)
mercury; free radical
generation; binding to
thiols in enzymes and
structural proteins
Elemental Mercury
Dental amalgams,
fossil fuels, old latex
paint, thermometers,
incinerators,
occupational
75-85 percent of
vapor absorbed
Lipophilic, distributed
throughout body;
crosses blood-brain
and placental barriers;
accumulates in brain,
kidney
Oxidized intracellularly
to inorganic mercury
by catalase and
hydrogen peroxide
Urine, feces, sweat
and saliva
Oxidation to inorganic
(divalent) mercury
Inorganic Mercury
Demethylation of
methylmercury by
intestinal microflora;
biological oxidation of
elemental mercury
7-15 percent of
ingested dose
absorbed; 2-3
percent of dermal
dose absorbed in
animals
Does not cross
blood-brain or
placental barrier;
found in brain of
neonates;
accumulates in
kidney
Methylated by
intestinal microflora;
binds and induces
metallothionein
biosynthesis
Urine, bile, feces,
sweat, saliva
Binding to thiols in
enzymes and
structural proteins
Page 460 Alternative Medicine Review
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Ethylmercury (fungicides, thimerosal in
vaccines, and gamma-globulin) also causes renal
and central nervous system toxicity and is depos-
ited in the liver, kidneys, skin, brain, spleen, and
plasma.
7
Ethylmercury, like methylmercury, is me-
tabolized to the inorganic form and accounts for
50 percent of the mercury eliminated in urine.
Ethylmercury may actually be converted to inor-
ganic mercury in the tissues in greater amounts
and more rapidly than methylmercury.
7
As with
methylmercury, the feces are the main natural route
of elimination. Table 1 summarizes the forms of
mercury and their pharmacokinetics.
Mechanisms of Mercury Toxicity
Mercury can cause biochemical damage
to tissues and genes through diverse mechanisms,
such as interrupting intracellular calcium homeo-
stasis, disrupting membrane potential, altering
protein synthesis, and interrupting excitatory
amino acid pathways in the central nervous sys-
tem.
19
Mitochondrial damage, lipid peroxidation,
microtubule destruction,
20
and the neurotoxic ac-
cumulation of serotonin, aspartate, and glutamate
are all mechanisms of methylmercury neurotox-
icity.
19
Over time, both methylmercury and el-
emental mercury vapor in the brain are trans-
formed to inorganic mercury, and become firmly
bound to sulfhydryl-containing macromolecules.
21
Both methylmercury and inorganic mercury bind
to various molecular weight thiol-containing pro-
teins (glutathione, cysteine, albumin, etc.). The
binding and dissociation of these mercury-thiol
complexes are believed to control the movement
of mercury and its toxic effects in the body.
7
Mitochondrial damage from oxidative
stress may be the earliest sign of neurotoxicity with
methylmercury. A study in neural tissue indicates
the electron transport chain appears to be the site
where free radicals are generated, leading to oxi-
dative damage induced by methylmercury.
19
Mercury-Thiol Binding
Because the stability constants (energy
necessary to form and break bonds) for mercury
and thiol complexes (glutathione, albumin,
cysteine, etc.) are so high, mercury will bind to
any free thiol available and the thiol in the highest
concentration will be the most frequently-bound.
22
The reaction rate is almost instantaneous.
7
Although the mercury-sulfhydryl bond is stable,
it is labile in the presence of other free sulfhydryl
groups; therefore, methylmercury will be
redistributed to other competing sulfhydryl-
containing ligands.
23
This is the basis for chelation
of heavy metals with sulfhydryl compounds like
DMPS and DMSA – providing free sulfhydryl
groups in high concentrations to encourage the
metal to move from one sulfhydryl-containing
ligand to another.
The endogenous thiol-containing mol-
ecules – glutathione, cysteine, homocysteine,
metallothionein, and albumin – all contain reduced
sulfur atoms that bind to mercuric ions and deter-
mine the biological fate of mercury compounds
in the body.
24
The complex of methylmercury and
cysteine may act as a “molecular mimic” for the
amino acid methionine and gain entry into the
central nervous system via the same mechanism
methionine uses to cross the blood-brain barrier.
25
Endogenous thiols transport mercury compounds
and act to protect them from binding to other pro-
teins, preventing functional damage in that tissue.
In general, the higher the cysteine or thiol con-
centration in a cell medium, the lower the con-
centration of intracellular divalent mercury. In
other words, higher concentrations of thiols ap-
pear to protect against accumulation of mercury,
both in vivo and in vitro.
22
Glutathione in Heavy Metal
Binding
Glutathione is the most common low-
molecular weight sulfhydryl-containing
compound in mammalian cells, present in
millimolar amounts in most cells.
26
As a result of
the binding of mercury to glutathione and the
subsequent elimination of intracellular glutathione,
levels of reduced glutathione are lowered in
several specific types of cells on exposure to all
forms of mercury. Glial cells,
27
human
erythrocytes,
28
and mammalian renal tissue
24
have
all been found to have significantly lowered levels
Alternative Medicine Review
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of reduced glutathione, a major source of oxidant
protection. Mercury, as well as cadmium,
generates highly toxic hydroxyl radicals from the
breakdown of hydrogen peroxide, which further
deplete glutathione stores.
27
There is evidence that
glutathione depletion can lead to neurological
damage; low levels of glutathione have been found
in Parkinson’s disease and cerebral ischemia-
reperfusion injury.
29
Glutathione, as both a carrier of mercury
and an antioxidant, has three specific roles in pro-
tecting the body from mercury toxicity. First, glu-
tathione, specifically binding with methylmercury,
forms a complex that prevents mercury from bind-
ing to cellular proteins and causing damage to both
enzymes and tissue.
30
Glutathione-mercury com-
plexes also reduce intracellular damage by pre-
venting mercury from entering tissue cells and
becoming an intracellular toxin.
Second, glutathione-mercury complexes
have been found in the liver, kidney, and brain,
and appear to be the primary form in which mer-
cury is transported and eliminated from the body.
24
The transport mechanism is unclear, but com-
plexes of glutathione and mercury are the predomi-
nant form of mercury in both the bile and the
urine.
31
Glutathione and cysteine, acting as carri-
ers of mercury, actually appear to control the rate
of mercury efflux into bile; the rate of mercury
secretion in bile appears to be independent of ac-
tual bile flow. When bile flow rate is increased or
decreased, the content of mercury in the bile
changes inversely so net mercury efflux from the
liver remains unchanged.
32
However, increasing
bile levels of both glutathione and cysteine in-
creases the biliary secretion of methylmercury in
rats.
13
Other studies have confirmed this data in
animal models.
33-35
Conversely, glutathione deple-
tion inhibits biliary secretion of methylmercury
in animal models and blocking glutathione pro-
duction appears to shut down biliary release of
mercury.
35
Cells of the blood-brain barrier (brain cap-
illary endothelial cells) release mercury in a gluta-
thione complex. Inhibiting glutathione production
in these cells inhibits their ability to release mer-
cury.
23
Mercury accumulates in the central nervous
system primarily in astrocytes, the cells that pro-
vide the first line of defense for the central ner-
vous system against toxic compounds.
36
Astrocytes
are the first cells in brain tissue to encounter met-
als crossing the blood-brain barrier. They also
contain high levels of metallothionein and gluta-
thione, both carriers for heavy metals. It is hy-
pothesized that astrocytes are the main depot of
mercury in the brain.
37
In studies with astrocytes,
the addition of glutathione, glutathione stimula-
tors, or glutathione precursors significantly en-
hances the release of mercury from these cells in
a complex with glutathione. Fujiyama et al
38
also
suggest that conjugation with glutathione is the
major pathway for mercury efflux from astrocytes.
Glutathione also increases mercury elimination
from renal tissue. Studies in mammalian renal cells
reveal glutathione is 50 percent as effective as the
chelating agent DMSA (2,3-dimercaptosuccinic
acid) in preventing inorganic mercury accumula-
tion in renal cells.
39
Third, glutathione increases the antioxi-
dant capacity of the cell, providing a defense
against hydrogen peroxide, singlet oxygen, hy-
droxyl radicals, and lipid peroxides produced by
mercury.
30
The addition of glutathione to cell cul-
tures exposed to methylmercury also prevented
the reduction of cellular levels of glutathione per-
oxidase, a crucial antioxidant enzyme necessary
for protection against the damaging effects of lipid
peroxidation.
30
As an antioxidant, glutathione appears to
protect against renal damage resulting from inor-
ganic mercury toxicity. The co-incubation of rat
renal cells with glutathione and inorganic mercury
was significantly more protective of renal cell in-
jury when compared to inorganic mercury expo-
sure alone.
40
Antioxidant levels – specifically glu-
tathione, vitamin E, and ascorbic acid – are de-
pleted in renal tissue exposed to mercuric chlo-
ride (inorganic mercury), and the addition of glu-
tathione increased levels of both vitamin E and
ascorbic acid in renal cells exposed to mercuric
chloride.
24
Mammalian cell lines resistant to mercury
toxicity have been cloned.
41
They do not readily
accumulate mercury and are resistant to the toxic
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effects of methylmercury or inorganic mercury.
An outstanding characteristic of this cell line is
that glutathione levels are five times greater in
these cells than the parent cells from which they
originated. The authors of this study conclude that
the mechanisms of resistance were primarily due
to glutathione’s ability to facilitate mercury efflux
from cells and the protective binding of mercury
by glutathione to prevent cellular damage.
The Role of alpha-Lipoic Acid
In 1966, German physicians began using
alpha-lipoic acid (ALA) therapeutically in patients
with diabetic polyneuropathy and liver cirrhosis
because of their observation that these patients had
lower levels of circulating lipoic acid.
42
The ap-
plication was subsequently extended to heavy
metal intoxication and toxic mushroom poisoning.
According to Jones and Cherian,
43
an ideal
heavy metal chelator should be able to enter the
cell easily, chelate the heavy metal from its com-
plex with metallothionein or other proteins, and
increase the excretion of the metal without its re-
distribution to other organs or tissues. Although
no human clinical trial has investigated the use of
ALA as a chelating agent in mercury toxicity, there
is evidence ALA satisfies at least two of the above
criteria; i.e., absorption into the intracellular en-
vironment and complexing metals previously
bound to other sulfhydryl proteins.
ALA produced endogenously is bound to
proteins, but can also be found unbound in the cir-
culation, after exogenous lipoic acid supplemen-
tation.
41
In this form it is chemically able to trap
circulating heavy metals, thus preventing cellular
damage caused by metal toxicity.
41
Lipoic acid is
lipophilic and is able to penetrate cell membranes
and reach high intracellular concentrations within
30 seconds of its administration.
44
The fact that free ALA crosses the blood-
brain barrier is significant because the brain readily
accumulates lead and mercury, where these met-
als are stored intracellularly in glial tissue.
36,45
Oral
doses of 10 mg/kg ALA in rats have reached peak
levels in the cerebral cortex, spinal cord, and pe-
ripheral nerves within 30 minutes of administra-
tion, and studies of chronic daily dosing conclude
ALA reaches all areas of the CNS and peripheral
nervous system.
46
ALA has been shown to decrease
lipid peroxidation in brain and sciatic nerve tis-
sue
47
and when given orally to rats, decreased lipid
peroxidation in brain tissue by 50 percent.
46
In
diabetic neuropathy, free lipoic acid may prevent
glucose-related oxidative damage by entering
nerve tissue where it acts as both an antioxidant
and heavy metal-binding agent.
28
ALA has been administered to humans in
doses up to 1,200 mg intravenously without tox-
icity, and in oral daily doses of as much as 600
mg three times daily. The only side effects reported
are infrequent nausea and vomiting. No side ef-
fects have been reported in oral administration of
up to 1,800 mg daily.
41,48
Doses of 500-1,000 mg
have been well tolerated in placebo-controlled
studies.
49
Extrapolation of pharmacokinetic and
toxicity data demonstrate safe human dosages
would not be exceeded with oral doses of several
grams per day.
41
ALA has been shown to increase both in-
tra- and extracellular levels of glutathione in T-
cell cultures, human erythrocytes, glial cells, and
peripheral blood lymphocytes.
50
In rats, oral dos-
ing of 150 mg/kg/day for eight weeks significantly
increased glutathione levels in the blood and
liver.
51
ALA has been shown to increase intracel-
lular glutathione by 30-70 percent in murine neu-
roblastoma and melanoma cell lines, and in the
lung, liver, and kidney cells of mice that had re-
ceived intraperitoneal injections of 4, 8, or 16 mg/
kg ALA for 11 days.
52,53
Levels of intracellular
glutathione have been shown to increase by 16
percent in T-cell cultures at concentrations of 10-
100 µM (concentrations achievable with oral and
intravenous supplementation of ALA).
50
A single
oral dose of 600 mg ALA was able to produce a
serum concentration of 13.8 ± 7.2 µM and levels
of 100-200 µM have been reported after 600 mg
intravenous administration.
54
Increases in glutathione levels seen with
ALA administration are not only from the reduc-
tion of oxidized glutathione (one of the functions
of ALA) but also from the synthesis of gluta-
thione.
46
ALA is reduced to dihydrolipoic acid
Alternative Medicine Review
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(DHLA), itself a potent antioxidant. DHLA is able
to regenerate oxidized ascorbate, glutathione, co-
enzyme Q, and vitamin E,
28
and is responsible for
the ability of ALA to increase intracellular gluta-
thione levels (Figure 1).
55
ALA, through its reduction to DHLA and
oxidation back to ALA, has the ability to
continuously provide cysteine, the rate-limiting
amino acid for glutathione production. ALA is
rapidly reduced to DHLA and released in the
extracellular environment where it reduces
extracellular cystine to cysteine and increases the
uptake of cysteine into the cell,
50
increasing
glutathione production. ALA does this through
enzyme-catalyzed reactions using NADH or
NADPH, the metabolic power resulting from
glucose metabolism (Figure 2).
51
ALA and Binding of Copper, Iron,
Platinum, and Lead
ALA and DHLA have been shown to form
complexes with manganese (Mn2
+
), zinc (Zn2
+
),
cadmium (Cd2
+
), lead (Pb2
+
), cobalt (Co2
+
), nickel
(Ni2
+
), and iron (Fe2
+
) ions.
55
In many cases, ALA-
mediated heavy-metal binding prevents free-
radical caused tissue damage or enzyme
inactivation.
56
Figure 1. Antioxidant Recycling
Dihydrolipoic Acid
CH
2
CH
2
CH
2
CH
2
CH
2
CH
2
CH
2
SH
COOH
SH
CH
2
CH
2
CH
2
CH
2
CH
2
CH
2
CH
2
S
S
COOH
α - Lipoic Acid
A
LA is reduced to DHLA and regenerates glutathione from oxidized glutathione. DHLA also
recycles vitamin C from oxidized ascorbate, consequently restoring vitamin E.
1.
2.
3.
GSSG
GSH
DHLA
LA
DHLA
LA
DHAA
AA
Vit E
Vit E
radical
Page 464 Alternative Medicine Review
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Mercury Toxicity Review
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In the case of iron and copper, complexing
with ALA can protect cells from damage caused
by iron- or copper-induced lipid peroxidation.
41
ALA has been shown to bind copper in human
lipoproteins
57
and, as a result, to inhibit copper-
induced peroxidation of low density lipoproteins.
ALA has been used to treat Wilson’s disease, ef-
fectively increasing renal copper excretion and
normalizing liver function.
58
ALA is also able to form complexes with
ferritin-bound iron both in vitro and in vivo.
59
ALA
has the ability to displace protein or vitamin C
bound to iron and bind to Fe2
+
. DHLA can facili-
tate the release of iron from the ferritin molecule
and bind iron.
41
The brain, particularly the substantia ni-
gra and the globus pallidus, contains high levels
of iron.
46
The high iron content and an increased
level of unsaturated fatty acids lead to increased
levels of tissue peroxidation.
46
ALA has been found
to suppress the free radicals initiated by reactions
with iron in the substantia nigra and other parts of
the CNS.
46
ALA has also been shown to protect
against cisplatin-induced renal damage in rats by
binding to platinum that is responsible for renal
toxicity.
60
At dosages of 25-100 mg/kg (equivalent
to 7 grams per 70 kg human adult), ALA restored
normal levels of antioxidant enzyme activity,
increased reduced glutathione levels, and
significantly decreased renal tissue platinum
content. The dose of cisplatin used in the study
(16 mg/kg) is similar to clinical use in cancer
treatment. Although the potential toxicity of this
high dose of ALA is unknown, it is much higher
than the 300-1800 mg typically used
clinically.
46,48,49
An intraperitoneal injection of 25 mg/kg
ALA given to rats for seven days was able to sig-
nificantly alter the oxidative stress induced by lead
toxicity.
61
ALA administration increased gluta-
thione levels 207 percent in the lead-exposed rats
and decreased malondialdehyde levels in the brain,
kidneys, and red blood cells, three of the four main
targets of lead toxicity.
61
Further studies in cell
lines of the fourth target, the reproductive system,
found ALA had a protective effect in hamster ova-
rian cells, decreasing oxidative stress that causes
cellular damage and death as a result of lipid
peroxidation.
61
Because lead exposure was high
(2,000 ppm injected daily into rats for five weeks)
and the length of time ALA was administered was
short (seven days), there may not have been
Figure 2. Reduction of ALA to DHLA and Cystine to Cysteine
Lipoic
Acid
Dihydrolipoic
Acid
Cystine
2 Cysteine Cysteine
Dihydrolipoic
Acid
Lipoic
Acid
NADPH, NADH
NADP
+
, NAD
+
γ-glutamyl cysteine synthetase
glutathione synthetase
GSH
Alternative Medicine Review
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Review Mercury Toxicity
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enough time to see decreases in levels of lead in
the brain or kidneys, if that effect were to take
place. There were significant improvements in cell
viability in ovarian cells exposed to lead that did
not result from direct ALA-iron binding, suggest-
ing ALA has a protective effect in lead toxicity
aside from its ability to bind and excrete lead.
61
ALA and Cadmium, Arsenic, and
Mercury
Cadmium, arsenic, and mercury toxicity
all involve similar pathways of cellular damage;
i.e., mitochondrial damage, inhibition of mito-
chondrial enzymes, suppression of protein synthe-
sis, and production of free radicals.
62
All three have
a strong affinity for sulfhydryl-containing ligands
(glutathione, alpha-lipoic acid, etc.), and each re-
sult in depressed levels of reduced glutathione.
63
The efficacy of ALA as an antioxidant and heavy
metal-complexing agent in cadmium, arsenic, and
mercury toxicity has been studied in animals –
with results that may be applicable to heavy metal
toxicity in humans.
ALA, at concentrations of 5 mM, was able
to protect rat hepatocytes from cadmium toxicity
(200 µM) by preventing decreases in total glu-
tathione and increases in lipid peroxidation.
63
An-
other cadmium study investigated 1.5-6.0 mM
concentrations of ALA or 17-89 µM DHLA in rat
hepatocytes exposed to cadmium.
64
Both proto-
cols decreased cadmium uptake by hepatocytes
and normalized hepatocyte glutathione levels,
leading to increased cell viability and survival
despite the cadmium toxicity. ALA has also been
shown (at a 30 mg/kg injected dose) to completely
prevent damage that occurs from cadmium-in-
duced lipid peroxidation in rat brain, heart, and
testes.
65
In addition, ALA completely restored glu-
tathione levels in the rat brain that had declined
63 percent with cadmium exposure.
A frequently quoted article referring to
ALA as a heavy metal-complexing agent is the
study by Grunert.
66
Published in 1960, the inves-
tigation used a dog and rat model in which simul-
taneous injection of sodium arsenate and ALA in
both animals protected them from fatal arsenic
toxicity. It has been shown that in acute arsenic
intoxication, lipoic acid can form a complex with
arsenic that renders the arsenic nontoxic.
41
Stud-
ies dosing mice with arsenic have shown ALA
prevents intestinal uptake of arsenic and reduces
the toxic effect of arsenic on enzyme inhibition.
49
ALA has been shown to affect the release
of glutathione into bile secretions. In animal stud-
ies, increasing amounts of glutathione in bile has
been shown to dramatically increase the release
of inorganic mercury. ALA given intravenously
to rats at doses of 37.5-300 µM/kg was shown to
increase inorganic mercury release in bile by
1,200-4,000 percent immediately after mercury
exposure.
67
Levels of released inorganic mercury
remained at a 300-700 percent elevation, even
three hours after dosing with ALA. If mercury was
injected 24 hours prior to the administration of
ALA, the increase in release of inorganic mercury
was substantially less, but was still elevated 140-
330 percent. A lower dose of ALA (37.5 µM/kg)
was more effective than higher doses at increas-
ing the biliary elimination of methylmercury.
There was disconcerting evidence from
this study, however, that ALA may also alter the
tissue distribution of mercury and other heavy
metals.
Although levels of inorganic mercury and
methylmercury in the kidney dropped signifi-
cantly, levels of inorganic mercury also increased
significantly in the brain, lung, heart, and liver tis-
sue. Methylmercury levels had also increased in
the brain, intestine and muscle of the rats given
ALA. The same phenomenon occurred in rats ex-
posed to cadmium and given the same doses of
ALA. Levels of cadmium in the liver dropped
(where cadmium is most frequently stored) but
increased in the kidney and muscle. The same was
true in rats given copper and ALA; all tissues ex-
amined had increased levels of copper, except for
the liver (where copper usually accumulates)
where levels had dropped.
67
In all cases the pat-
tern was the same; the tissues that concentrated
the metal (blood, spleen, and kidneys in the case
of methylmercury) had reduced concentrations,
while other tissues appeared to have a greater con-
centration.
Page 466 Alternative Medicine Review
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Mercury Toxicity Review
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Grunert subjected mice to lethal doses of
mercuric chloride accompanied with ALA.
66
He
found the ALA-to-mercury ratio was crucial in
determining the outcome. A ratio of 6-8 moles
ALA per mole mercuric chloride was necessary
to allow the mice to survive mercury poisoning. A
lower level of ALA actually increased the mer-
cury toxicity (a molar ratio of 2 moles ALA to 1
mole mercuric chloride or lower) above control
levels. The level of mercuric chloride used in this
experiment, 20 mg/kg, is high and would only be
seen in acute mercury poisoning.
In another study of mercury intoxication,
an injection of 10 mg/kg/day ALA in rats given
an injection of 1 mg/kg/day mercuric chloride
prevented damage to nerve tissue caused by lipid
peroxidation.
68
ALA significantly reduced lipid
peroxidation in the mercury-exposed rats while
elevating levels of the antioxidants glutathione,
ascorbate, and tocopherol. The mechanism of
protection was hypothesized to be the scavenging
of peroxyl radicals formed in the brain and
nervous system, although the authors believed
direct complexing of inorganic mercury by ALA
was also a possibility.
ALA versus Dithiol-based Chelating
Agents (DMPS, DMSA)
The ability of ALA to bind inorganic
mercury from rabbit renal tissue was compared
to glutathione and the chelators 2,3-
dimercaptopropane-1-sulfonate (DMPS), meso-
2,3-dimercapto- succinic acid (DMSA), peni-
cillamine, and ethylenediaminetetra acetic acid
(EDTA) (Figure 3).
69
DMPS was the most efficient chelator,
removing 86 percent of the mercury in three
hours, with DMSA being the next-most efficient,
removing 65 percent of the mercury. In the same
time period, penicillamine removed 60 percent,
glutathione removed 50 percent, ALA removed
35 percent, and EDTA removed 20 percent. Only
the levels reached by DMSA and DMPS, how-
ever, were statistically significantly different
from baseline (p<0.05). Therefore, the effect of
ALA and glutathione may show only a trend or
an apparent effect and are not comparable to
DMPS and DMSA. Although the actual effect of
a chelator or heavy metal-complexing agent can-
not be determined in a three-hour time period, and
acute doses of 10 mg/kg of inorganic mercury
would be considered highly toxic in an adult hu-
man, there is evidence from this study that ALA
is a less efficient binder of inorganic mercury than
the recognized chelating agents, DMSA and
DMPS. All of the substances were used at a con-
centration of 10 mM, a level difficult to reach with
ALA oral supplementation.
In another comparison study, ALA (25
mg/kg/day) resulted in an insignificant decrease
in blood and tissue lead in rats with lead toxicity
when compared to the dithiol-based chelating
agent, DMSA (dosed at 90 mg/kg/day) (Table 2).
61
Figure 3. Ability of Chelating Agents to
Lower Mercury Content of Renal Tissue in
vitro from Rabbits Injected with Mercuric
Chloride
Control
10 mM EDTA
10 mM LA
10 mM GSH
10 mM PA
10 mM DMS
A
10 mM DMPS
1000
800
600
400
200
0
0123
Time
(
hours
)
Hg, ng/cm
2
Alternative Medicine Review
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Review Mercury Toxicity
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Both DMSA
and DMPS have been
shown to be clinically
effective heavy metal
chelators in human
studies of mercury
toxicity,
70-75
particu-
larly since they both
chelate inorganic and
organic mercury.
71
DMSA acts only as an
extracellular chelator,
whereas DMPS enters
hepatocytes
73
and re-
nal cells,
76
although it
is still considered primarily an extracellular che-
lator.
73
DMSA is less toxic because of its inability
to enter cells or bile,
73
with an LD
50
of 13.73 mM/
kg, approximately twice the LD
50
of DMPS, which
is 6.53 mM/kg.
73
While DMSA has been found to
be more effective than DMPS at removing mer-
cury from the brain,
77
DMPS appears to be more
effective at removing mercury from the kidney.
78
Conclusion
Many unanswered questions remain re-
garding ALA and heavy metal detoxification, es-
pecially pertaining to mercury. The amount of
ALA supplemented versus the amount of toxic
metal stored in the tissues is important, and has
been clearly detailed in animal trials. A molar ra-
tio of 6-8:1 (ALA:mercury) is necessary for pro-
tection and viability in mercury studies; a ratio of
2:3 has been seen in arsenic studies.
66
The ability
of ALA to assist or prevent movement of heavy
metals from the liver appears to be element-spe-
cific. In a previously mentioned study, the biliary
release of methylmercury, cadmium, zinc, and cop-
per was inhibited by ALA.
69
The evidence that ALA may mobilize
heavy metals to other tissues from tissues where
the metals are most concentrated, specifically the
brain, is troublesome. An explanation for this find-
ing may lie in the complexing of heavy metals
with glutathione and lipoic acid. Inorganic mer-
cury forms stable complexes with ALA or DHLA
and could be excreted with DHLA independent of
available glutathione.
67
As Gregus et al
67
hypoth-
esize, injected lipoic acid could complex with glu-
tathione as it passes through the liver, preventing
glutathione from carrying other heavy metals such
as cadmium, or transition metals such as zinc and
copper, into bile. Speculation aside, there is clear
evidence ALA and its reduced form DHLA have
the ability to act as both intra- and extracellular
heavy metal-complexing agents, with little known
toxicity and patterns of heavy metal mobilization
and transport not yet understood in humans. In
the absence of data from human trials, however, it
can only be suggested that ALA be used as an ad-
junct to chelation with the standard dithiols, DMPS
and DMSA.
Mercury toxicity is a significant clinical
entity, as it is ubiquitous in the environment and
poses serious risk to human health. The pathol-
ogy of mercury toxicity in humans is diverse and
encompasses direct damage to tissues and enzyme
function as well as indirect damage as a result of
oxidant stress.
Glutathione has been shown to be a sig-
nificant factor in heavy metal mobilization and
excretion, specifically with application to mercury,
cadmium, and arsenic. Glutathione depletion and
glutathione supplementation have specific effects
on mercury toxicity, both by altering antioxidant
status in the body and by directly affecting excre-
tion of mercury and other heavy metals in the bile.
Table 2. Blood Lead Levels from Fischer 344 Rats
Blood lead levels
(mcg/dL)
Control
0.2 ± 0.5
Pb only
36.4 ± 4.4*
Pb + LA
28.7 ± 4.1
Pb + DMSA
2.0 ± 1.0**
All values represent mean ± SD for 5-10 samples
*p < 0.001, compared to the corresponding value of control group
** p < 0.005, compared to the corresponding value of lead group
Page 468 Alternative Medicine Review
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Mercury Toxicity Review
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Lipoic acid has been shown, by its increas-
ing of cellular glutathione levels, to support the
mobilization and excretion of mercury, and to de-
crease cellular damage and neurotoxicity. The re-
duced form of ALA, DHLA, appears to have di-
rect heavy metal-binding effects. When compared
to pharmaceutical dithiol-chelating agents, ALA
appears to be able to bind and mobilize heavy
metals from tissue, although with much weaker
an effect.
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... Ao alcançar a circulação, o MeHg forma um complexo molecular intracelular devido a afinidade com o composto sulfidrila (SH), e, de acordo com Patrick (2002), o metilmercúrio atua exercendo função supressora sobre o crescimento celular ao inibir as atividades das proteínas pela saturação dos seus grupos sulfidrilas, podendo inativar os mecanismos enzimáticos fundamentais da oxidação celular. ...
... Outros danos bioquímicos são gerados pela ação do metilmercúrio por diversos mecanismos, como interrupção da homeostase do cálcio intracelular, alteração do potencial de membrana, alteração da síntese de proteínas, severo dano mitocondrial, apoptose, estresse oxidativo, rompimento ou comprometimento da polimerização de microtúbulos e consequente aberrações cromossômicas (PATRICK, 2002;SILVA, 2014). Efeitos na rede estrutural de microtúbulos, podendo causar desarranjos na distribuição de cromossomos e a ação indireta ao material genético, principalmente através da indução da geração de espécies reativas de oxigênio (EROS), caracterizam a ação genotóxica do MeHg (CANO, 2014). ...
... It is used in industries like paints, cosmetics, batteries, electrical industries, etc. In pharmaceuticals, it is used in thermometers, barometer, dental amalgams, nuclear reactor, etc. (Patrick 2002). Exposure to mercury can occur in many ways, it can be accidental, agricultural or through food which is contaminated by mercury (Dopp et al., 2004). ...
... Organic and elemental forms are more toxic as they can easily bypass the placental barrier and blood-brain barrier. Thus, gets deposited inside kidney (Patrick, 2002) and brain (Clarkson et al., 2003). It affects the body in different ways such as memory loss, hair loss, loss of vision and many autoimmune diseases (Dixit et al., 2015). ...
Chapter
Environmental pollution is a serious issue faced by the present world. Due to lack of waste management, industrial effluents are directly disposed into rivers. Among all pollutants, heavy metals are amongst dangerous ones because of their adverse effects on mankind. Water pollution by heavy metals has become a global issue that needs considerable attention to combat its harmful effects. Since industrialization, human intervention has been increasingly affecting our environment. The common heavy metals that have been identified in polluted water include arsenic, lead, mercury, chromium and cadmium. Persistence and biomagnification of these metals in nature present a significant threat to public health and safety. The danger of heavy metal pollutants in water lies in two categories. Firstly, heavy metals can persist in natural ecosystems for an extended period. Secondly, they can accumulate in successive levels of biological chain, thereby causing cardiovascular, central nervous system, renal, endocrinological, reproductive, neurological, developmental and immunological disorders. Removal of heavy metal contaminants from wastewater using microorganisms like algae, fungi or bacteria has a great potential. The process of abatement of heavy metals with the help of bioremediators like algae is known as phycoremediation. It is a clean-green technology which is an easy, safe and economical solution. In this chapter, adverse effects of the heavy metals on human health and remediation of heavy metals with the help of microalgae have been discussed in detail.
... HgCl2 produces oxidative stress and alterations in the redox environment by three mechanisms: Fenton and Haber-Weiss reactions that generate free radicals and ROS [17], the activation of ER stress [3], and the binding of Hg 2+ with intracellular sulfhydryl-containing proteins and low-molecular-weight compounds (e.g., GSH) capable of affecting the redox environment and protein function [18]. As a consequence of these reactions, nephrin and podocin are downregulated, and the slit diaphragm is injured, which is observed as HgCl2-induced AKI. ...
... Thus, the aim of the current contribution was to explore the molecular mechanism of action of C-PE (purified from P. persicinum) by examining its nephroprotective activity against HgCl 2 -induced ER stress, oxidative stress, and alterations in the redox environment in the same animal model. HgCl 2 produces oxidative stress and alterations in the redox environment by three mechanisms: Fenton and Haber-Weiss reactions that generate free radicals and ROS [17], the activation of ER stress [3], and the binding of Hg 2+ with intracellular sulfhydrylcontaining proteins and low-molecular-weight compounds (e.g., GSH) capable of affecting the redox environment and protein function [18]. As a consequence of these reactions, nephrin and podocin are downregulated, and the slit diaphragm is injured, which is observed as HgCl 2 -induced AKI. ...
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C-phycoerythrin (C-PE) is a phycobiliprotein that prevents oxidative stress and cell damage. The aim of this study was to evaluate whether C-PE also counteracts endoplasmic reticulum (ER) stress as a mechanism contributing to its nephroprotective activity. After C-PE was purified from Phormidium persicinum by using size exclusion chromatography, it was characterized by spectrometry and fluorometry. A mouse model of HgCl2-induced acute kidney injury (AKI) was used to assess the effect of C-PE treatment (at 25, 50, or 100 mg/kg of body weight) on oxidative stress, the redox environment, and renal damage. ER stress was examined with the same model and C-PE treatment at 100 mg/kg. C-PE diminished oxidative stress and cell damage in a dose-dependent manner by impeding the decrease in expression of nephrin and podocin normally caused by mercury intoxication. It reduced ER stress by preventing the activation of the inositol-requiring enzyme-1α (IRE1α) pathway and avoiding caspase-mediated cell death, while leaving the expression of protein kinase RNA-like ER kinase (PERK) and activating transcription factor 6α (ATF6α) pathways unmodified. Hence, C-PE exhibited a nephroprotective effect on HgCl2-induced AKI by reducing oxidative stress and ER stress.
... MeHg functions as a neurotoxin, responsible for the buildup of amino acid such aspartate, serotonin, and glutamate. In addition to MeHg buildup, impairment of normal microtubule formation and mitochondrial dysfunction and initiation of lipid peroxidation have been reported by Patrick [76]. According to Rowland [77], some fraction of intestinal gut microorganisms may come in contact with MeHg which have the capacity of breaking carbon-Hg bond and converting it to inorganic Hg. ...
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Full-text available
The gut microbiota has a vital role in the maintenance of intestinal homeostasis. Several studies have revealed that environmental exposure to pollutants such as heavy metals may contribute to the progression of extensive list of diseases which may further lead to perturbations in the gut leading to dysbiosis. This manuscript critically reviews the alterations in the gut microbiota composition and function upon exposure to various toxic heavy metals prevalent in the environment. The disturbance in gut microbial ecology also affects the microbial metabolic profile which may alter the speciation state and bioavailability heavy metals thus affecting metal uptake—absorption/detoxification mechanisms associated to heavy metal metabolism. The toxic effects of various heavy metals either in single or in multimetallic combination and the gut microbiota associated host health and disease condition need a comprehensive assessment with important consideration for therapeutic and protective strategies against the damage to gut microbiota.
... Any change in these enzymes indicates the presence of heavy metal pollution in the environment (Paithankar et al., 2021). Exhaustion of the antioxidant systems may be attributed to the binding of Hg to the thiol groups of antioxidant enzymes (SOD, CAT and GPx), impairing the ability of these enzymes to neutralize ROS (Patrick, 2002). The present study results revealed a substantial decrease in TAC and SOD, as well as a significant increase in MDA in O. niloticus exposed to Hg. ...
... Any change in these enzymes indicates the presence of heavy metal pollution in the environment (Paithankar et al., 2021). Exhaustion of the antioxidant systems may be attributed to the binding of Hg to the thiol groups of antioxidant enzymes (SOD, CAT and GPx), impairing the ability of these enzymes to neutralize ROS (Patrick, 2002). The present study results revealed a substantial decrease in TAC and SOD, as well as a significant increase in MDA in O. niloticus exposed to Hg. ...
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The study's objective was to evaluate using olive stone biochar (OSB), an inexpensive agro-waste product, to adsorb and remove inorganic mercury from Nile tilapia (Oreochromis niloticus) aquaculture systems. First, the OSB's adsorption capacity was evaluated by testing different concentrations: 1, 2 and 3 g L⁻¹ for 0, 24, 48, 72 and 120 h. The concentration of Hg decreased with increasing OSB concentration up to 48 h, with the highest Hg adsorption rate observed at 2 g OSB L⁻¹. An experimental study assessed the OSB's impact on Nile tilapia immune status and growth efficiency. The experiment used 180 Nile tilapia divided into four treatment groups (CONT, OSB, Hg and Hg +OSB), with three replicates per treatment. Fish were fed a normal basal diet twice daily for 60 d. The CONT group served as a control without any treatment. The OSB group was exposed to 2 g OSB L⁻¹ of water, the Hg group was exposed to 0.084 mg Hg L⁻¹, and the Hg +OSB group was exposed to 0.084 mg Hg L⁻¹ with 2 g OSB L⁻¹. Hg exposure caused liver and renal dysfunction and reduced growth performance, haematological indices, total antioxidant capacity, superoxide dismutase and non-specific immune parameters. Adding OSB to the pond water reduced these effects. In conclusion, adding 2 g OSB L⁻¹ to aquarium water and changing it every 48 h mitigates the immunosuppressive effects of sub-chronic mercury toxicity and lowers mercury residues in fish muscle.
... It has multiple essential purposes in the cellular environment, among them binding metal ions, both essential ones such as copper (Cu) 1,2 and zinc (Zn) 3,4 and toxic ones such as cadmium (Cd) 5 and mercury (Hg). 6 In the latter case, GSH participates in Hg detoxification by several mechanisms. 7,8 GSH also weakly binds lead (Pb), 9−11 but the ability of the peptide to reduce Pb toxicity is marginal. ...
Article
The natural tripeptide glutathione (GSH) is a ubiquitous compound harboring various biological tasks, among them interacting with essential and toxic metal ions. Yet, although weakly binding the poisonous metal lead (Pb), GSH poorly detoxifies it. β-Mercaptoaspartic acid is a new-to-nature novel amino acid that was found to enhance the Pb-detoxification capability of a synthetic cyclic tetrapeptide. Aiming to explore the advantages of noncanonical amino acids (ncAAs) of this nature, we studied the detoxification capabilities of GSH and three analogue peptides, each of which contains at least one ncAA that harbors both free carboxylate and thiolate groups. A thorough investigation that includes in vitro detoxification and mechanistic evaluations, metal-binding affinity, metal selectivity, and computational studies shows that these ncAAs are highly beneficial in additively enhancing Pb binding and reveals the importance of both high affinity and metal selectivity in synergistically reducing Pb toxicity in cells. Hence, such ncAAs join the chemical toolbox against Pb poisoning and pollution, enabling peptides to strongly and selectively bind the toxic metal ion.
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Polychlorinated diphenyl ethers (PCDEs) have been detected in various aquatic matrices, which pose potential threats to aquatic ecosystem security. In this work, both micro and macro analysis methods were used to assess the toxicity of PCDEs to zebrafish. Results indicated that after in vivo PCDE exposure, the oxidative stress and related gene of Danio rerio were significantly changed. The higher concentration or longer exposure time could cause more severe oxidative stress in zebrafish tissues. Compared with among the five tested compounds, more obvious changes in the level of oxidative biomarkers of lower chlorinated PCDEs’ (4-mono-CDE and 4,4′-di-CDE) exposure groups were observed. The integrated biomarker response analysis and gene expression results also indicate a similar trend. Histopathological observation suggested that 4,4′-di-CDE could render liver nuclei enlargement and necrosis, hepatocyte vacuolation, and the development inhibition of ovarian cells. Transmission electron microscope photos showed that 4,4′-di-CDE caused organelle damage in the liver and ovary, including the rupture of the endoplasmic reticulum, swelling of mitochondria, and condensation of chromatin in the liver and mitochondria disappeared significantly in the ovary. The degree of damage is enhanced with the increasing exposure doses. In addition, PCDEs also significantly altered vitellogenin content and related gene (vtg1) expression, suggesting that PCDEs may be estrogen endocrine disruptors. Overall, these results provided some valuable toxicological data of PCDEs on aquatic species.
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Beside partial coverage in three reviews so far (1994, 2009, 2019), there is no review on genotoxic studies dealing with mercury (Hg) and human exposure using the most usual genotoxic assays: sister chromatid exchanges (SCE), chromosomal aberrations (CA), cytochalasin B blocked micronucleus assay (CBMN), and single-cell gel electrophoresis (SCGE or alkaline comet assay). Fifty years from the first Hg genotoxicity study and with the Minamata Convention in force, the genotoxic potential of Hg and its derivatives is still controversial. Considering these antecedents, we present this first systematic literature overview of genotoxic studies dealing with Hg and human exposure that used the standard genotoxic assays. To date, there is not sufficient evidence for Hg human carcinogen classification, so the new data collections can be of great help. A review was made of the studies available (those published before the end of October 2021 on PubMed or Web of Science in English or Spanish language) in the scientific literature dealing with genotoxic assays and human sample exposure ex vivo, in vivo, and in vitro. Results from a total of 66 articles selected are presented. Organic (o)Hg compounds were more toxic than inorganic and/or elemental ones, without ruling out that all represent a risk. The most studied inorganic (i)Hg compounds in populations exposed accidentally, occupationally, or iatrogenically, and/or in human cells, were Hg chloride and Hg nitrate and of the organic compounds, were methylmercury, thimerosal, methylmercury chloride, phenylmercuric acetate, and methylmercury hydroxide.
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Dust is regarded as an important pathway of heavy metal(loid)s to the human body. Health risks posed by metal(loid)s from household dust are of particular concern. However, the contamination and sources of heavy metal(loid)s in household dust environments, as well as source identification of health risks related to heavy metal(loid)s from household dust for vulnerable populations such as children, have not been thoroughly studied in China, particularly for the areas involved with industrial activities such as ore mining. Thus, a cross-sectional study was conducted in a rural area famous for Pb/Zn ore mining, to assess the pollution sources and health risks of heavy metal(loid)s from household indoor and outdoor dust and to identify the contribution of household dust to the health risks for children. The results indicated that household environment was heavily contaminated by metal(loid)s, which were mainly attributed to mining activity. Meanwhile, the indoor/outdoor ratio and the redundancy analysis indicated that there were other pollution sources in indoor environments such as coal combustion, materials for interior building and decoration. Vapor inhalation was the main exposure pathway for Hg, while ingestion was the predominant pathway for other metal(loid)s. Although the cancer risks were relatively low, the HIt from household indoor and outdoor dust (2.19) was about twice the acceptable limit (1) and was primarily from Pb (64.52%) and As (23.42%). Outdoor dust was a larger contributor to the HI of Sb, As, Cr, Cd, Zn and Pb, which accounted for 51.37%, 58.63%, 52.14%, 59.66%, 52.87% and 64.47%, respectively, and the HIt was mainly from outdoor dust (60.76%). These results indicated that non-cancer health risks were largely from outdoor dust exposure, and strengthened the notion that concern should be given to the potential health risks from metal(loid)s in household dust both originating from mining activity and indoor environmental sources.
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The assumption of oxidative stress as a mechanism in lead toxicity suggests that antioxidants might play a role in the treatment of lead poisoning. The present study was designed to investigate the efficacy of lipoic acid (LA) in rebalancing the increased prooxidant/antioxidant ratio in lead-exposed Chinese hamster ovary (CHO) cells and Fischer 344 rats. Furthermore, LA's ability to decrease lead levels in the blood and tissues of lead-treated rats was examined. LA administration resulted in a significant improvement in the thiol capacity of cells via increasing glutathione levels and reducing malondialdehyde levels in the lead-exposed cells and animals, indicating a strong antioxidant shift on lead-induced oxidative stress. Furthermore, administration of LA after lead treatment significantly decreased catalase and red blood cell glucose-6-phosphate dehydrogenase activity. In vitro administration of LA to cultures of CHO cells significantly increased cell survival, that was inhibited by lead treatment in a concentration-dependent manner. Administration of LA was not effective in decreasing blood or tissue lead levels compared to a well-known chelator, succimer, that was able to reduce them to control levels. Hence, LA seems to be a good candidate for therapeutic intervention of lead poisoning, in combination with a chelator, rather than as a sole agent. © 1999 Elsevier Science Inc.
Article
Since the early nineteenth century, dentistry has relied mainly on amalgam (approximately 50% metallic mercury (Hg)) for filling teeth. Scientific research has shown that Hg is constantly released from amalgams, mainly as Hg vapour (Hgo),which is inhaled, absorbed, metabolized to ionic Hg (Hg2 + ) and distributed throughout the body, mainly bound to proteins. Dental amalgam is the major source of the body Hg burden. Toxicological research on amalgam Hg has indicated deleterious effects on the immune, renal, reproductive and central nervous systems, and oral and intestinal bacteria. Results do not indicate that amalgam fillings are safe. Oral DL-2,3-dimercapto-succinic acid, magnesium salt (DMSA); 2,3-dimercapto-1-propane-sulphonic acid, sodium salt (DMPS); N-acetyl-L-cysteine (NAC) and potassium citrate B.P. (K Cit.) were studied for Hg chelating ability in patients who had, or until recently had, amalgam fillings. Based on the increase in urinary Hg concentrations after single doses, compared with controls, the order of efficacy was: DMPS plus K Cit., NAC plus K Cit. and DMSA (each producing an increase of 163%), then in descending order, DMSA plus K Cit., DMPS, NAC and K Cit. Very significant (p 0.01) correlations were demonstrated between post-chelation urinary and post-chelation sweat Hg concentrations with all agents. Both these parameters may be good indicators of total body Hg burden. The advantages of employing combined chelating agents were examined and some clinically useful and convenient methods of assessing and reducing Hg burdens suggested.
Article
Mono-thiols can act either as pro- or anti-oxidants during metal-catalyzed low density lipoprotein (LDL) peroxidation, however investigation of the role of vicinal thiols has been neglected. Therefore dihydrolipoic acid (DHLA), a vicinal dithiol, and lipoic acid, its oxidized form, were used to investigate Cu2+-mediated LDL peroxidation. We demonstrate here that DHLA inhibited Cu2+-dependent LDL peroxidation by chelating copper. DHLA (0–20 μM) increased lag-times of conjugated diene formation in LDL (100 μg/ml) oxidized with 5 μM Cu2+ in a concentration dependent manner, and this effect was saturated after 5 μM DHLA; enough to chelate all of the added Cu2+. In a similar fashion DHLA prevented LDL-mediated reduction of Cu2+ to Cu+. Lipoic acid had no effect in these systems. DHLA alone also reduced Cu2+, however this was inhibited when DHLA was in excess of the copper concentration. Hence there is complex formation between the two species. Copper:DHLA complex formation was further investigated and found to be dependent upon pH and the presence of oxygen. At low pH (<6), or in the absence of oxygen, the complex is stable, presumably due to vicinal thiol chelation. As the pH is increased, the carboxylate group also participates in copper chelation, this results in a less stable complex which is susceptible to oxidation, and copper is eventually released. Electron spin resonance studies demonstrate the formation of hydroxyl, but not superoxide, radicals during Cu2+-catalyzed DHLA oxidation. Thus in our LDL experiments at physiological pH, DHLA is able to either reductively inactivate Cu2+ when Cu2+ is in excess, or effectively chelate Cu2+ when DHLA is in excess. The Cu2+:DHLA complex eventually undergoes copper-catalyzed oxidation, copper is released and LDL peroxidation proceeds. DHLA, thus, has both pro- and antioxidant properties depending upon the ratio of Cu2+:DHLA and the pH. These results provide an additional mechanism of thiol-mediated formation of radicals and metal chelation.
Article
Glutathione (GSH) has emerged to be one of the most fascinating endogenous molecules virtually present in all animal cells often in quite high (mM) concentrations. In addition to the detoxicant, antioxidant, and cysteine-reservoir functions of cellular glutathione, the potential of this ubiquitous thiol to modulate cellular signal transduction processes has been recently evident. Lowered tissue GSH levels have been observed in several disease conditions. Restoration of cell GSH levels in a number of these conditions have proven to be beneficial. Thus, strategies to boost cell glutathione level are of marked therapeutic significance. Availability of cysteine, a precursor for glutathione synthesis, inside the cell is a critical determinant of cellular glutathione level. N-acetylcysteine and α-lipoic acid are two pro-glutathione agents that have remarkable clinical potential. The ability of these two clinical drugs to enhance cellular glutathione level, coupled with their favorable effect on the molecular biology of HIV infection may make them useful tools for AIDS treatment.
Article
Four chelating agents that have been used most commonly for the treatment of humans intoxicated with lead, mercury, arsenic or other heavy metals and metalloids are reviewed as to their advantages, disadvantages, metabolism and specificity. Of these, CaNa2EDTA and dimercaprol (British anti-lewisite, BAL) are becoming outmoded and can be expected to be replaced by meso-2,3-dimercaptosuccinic acid (DMSA, succimer) for treatment of lead intoxication and by the sodium salt of 2,3-dimercapto-1-propanesulfonic acid (DMPS, DimavalR) for treating lead, mercury or arsenic intoxication. Meso-2,3-DMSA and DMPS are biotransformed differently in humans. More than 90% of the DMSA excreted in the urine is found in the form of a mixed disulflde in which each of the sulfur atoms of DMSA is in disulfide linkage with an l-cysteine molecule. After DMPS administration, however, acyclic and cyclic disulfides of DMPS are found in the urine. The Dimaval-mercury challenge test holds great promise as a diagnostic test for mercury exposure, especially for low level mercurialism. Urinary mercury after Dimaval challenge may be a better biomarker of low level mercurialism than unchallenged urinary mercury excretion.
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The brain is an organ that concentrates metals, and these metals are often localized to astroglia. An examination of metal physiology of brain cells, particularly astroglia, offers insights into the developmental neurotoxicity of certain metals, including lead (Pb), mercury (Hg), manganese (Mn), and copper (Cu). Xenobiotic metals probably accumulate in cells by exploiting the normal functions of proteins that transport and handle essential metals. In addition, essential metals may become toxic by accumulating at levels that exceed the normal metal buffering capacity of the cell. This review considers the uptake, accumulation, storage, and release of two xenobiotic metals, Pb and Hg, as well as two essential nutrient metals that are neurotoxic in high amounts, Mn and Cu. Evidence that each metal accumulates in astroglia is evaluated, together with the mechanisms the host cell may invoke to protect itself from cytoxicity.
Article
The neurotoxic effects of mercury (II) chloride, methylmercury (MeHg) and cadmium chloride on astrocytes were modelled using C6 glioma cell cultures. All three compounds were cytotoxic to these cells with an order of potency of cadmium > MeHg > mercurychloride. Addition of reduced glutathione (GSH) to the media protected the cells in all three cases, whereas depletion of GSH with l-buthionine-S,R-sulfoximine enhanced the toxicity of cadmium and mercury chloride but not MeHg. The effects of subcytotoxic concentrations of these compounds on intracellular GSH levels were assessed using chlorobimane staining. All three showed a similar type of effect-an initial depletion of GSH followed by an increase to levels greater than in untreated cells. For mercury chloride-exposed cells (0.37-3.7 muM), the initial depletion occurred over 4 hr with the cells recovering by 7 hr and increases in the GSH content seen after 24 hr. With cadmium or MeHg (0.04-4 muM), the initial depletion was more protracted, with treated cells having less GSH than control cells for 4-7 hr. Glutathione S-transferase activity in the cells was increased after 24 hr of exposure to all three metals to about 200% of control values. These results show that some components of the glutathione system in C6 glioma cells are activated after exposure to heavy metal compounds.
Article
http://deepblue.lib.umich.edu/bitstream/2027.42/51555/1/Salonen JT, Mercury Accumulation and Accelerated Progression, 2000.pdf
Article
This working paper summarizes the known ultrastructural and biochemical effects of lead, mercury, cadmium, and arsenic on subcellular organelle systems following in vivo administration. Documented metal-induced alterations in nuclear, mitochondrial, microsomal, and lysosomal functions are discussed in relation to their potential impact on cellular responses to other environmental agents. Each of the above elements has been found to interfere with normal cellular replication and genetic processes. Mitochondrial swelling and depression of respiratory function are discussed in relation to known metal-specific perturbations of mitochondrial heme biosynthetic pathway enzymes. Inhibition of microsomal enzyme activities and protein synthesis by lead and mercury is compared to the apparent absence of such effects following arsenic or cadmium exposure. Lysosomal uptake of all the metals is documented, but biochemical alterations in these structures have been reported for only mercury and cadmium. It is concluded that these toxic metals are capable of interacting with, and biochemically altering major cellular systems at dose levels below those required to produce signs of overt metal toxicity. The impact of these effects on cellular response to other metals and xenobiotics in complex exposure situations is presently unknown, and further research is urgently needed in this area.