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Science Index

Heavy Metal Detoxification


Chelation in metal intoxication. XXVIII: Effect of thiochelators on
mercury (II) toxicity: pre- and post treatment.
Khandelwal S; Kachru DN; Tandon SK
Industrial Toxicology Research Centre, Lucknow, India.
Biochem Int, 16(5):869-78 1988 May
The effect of treatment with alpha-mercapto-beta-(2-furyl)acrylic acid
(MFA), N-(N-mercaptopropionyl) glycine (MPG) and N-acetylcysteine (NAC)
compared to spironolactone (SPL), a steroid, before and after 203
mercury (II) exposure, on the disposition of Hg and induction of tissue
metallothionein (MT), was investigated in rats. The pretreatment with
SPL, MFA and MPG enhanced faecal elimination of Hg and reduced its
accumulation in liver particularly, the "heat stable fraction"
resulting in lowered hepatic MT induction. Neither the renal uptake of
Hg nor induction of tissue MT was affected by pre-treatment with the
chelating agents; SPL and MFA causing re-distribution of Hg among the
renal sub-cellular fractions. The post-Hg exposure treatment with MFA
enhanced the faecal and MPG the urinary excretion of Hg. However, both
the chelating agents increased the hepatic burden of Hg as reflected in
the subcellular fractions and increased MT contents indicating
mobilization of Hg from other tissue binding sites. The post-treatment
with MPG however, depleted renal Hg as reflected by the sub-cellular
distribution, without affecting renal MT levels. The results show that
MFA and MPG are more promising preventive than therapeutic agents in Hg
intoxication acting as metal chelators.

Involvement of glutathione in the enhanced renal excretion of methyl
mercury in CFW Swiss mice.
Mulder KM; Kostyniak PJ
Toxicol Appl Pharmacol, 78(3):451-7 1985 May
The present studies attempted to identify the mechanism for the
elevated urinary excretion rate for methyl mercury (MM) previously
reported in CFW Swiss mice. Strain comparisons of factors which could
conceivably influence renal excretion of MM were made. The
biotransformation of MM to the inorganic form did not appear to play a
significant role. No significant strain differences were observed in
the distribution of MM between plasma and red cells under in vivo or in
vitro conditions. The percentage of total plasma MM present in the
low-molecular-weight fraction did not differ statistically between the
CFW and CBA/J strains. Strain comparisons of total reduced nonprotein
thiol concentrations in liver, kidneys, whole blood, and plasma
revealed no significant strain differences. A significant strain
difference in plasma oxidized glutathione (GSSG) concentrations was
observed. However, plasma concentrations of reduced glutathione (GSH),
the form of glutathione (GS) which interacts with MM, did not
significantly vary between the strains. The rate of total glutathione
(TGS) excretion in urine was approximately 2-fold higher in CFW mice
than in CBA/J mice. The significantly higher urinary GS excretion in
CFW mice was accompanied by a 1.6-fold lower urinary
gamma-glutamyltranspeptidase (gamma-GTP) activity in this strain.

Effect of different renal glutathione levels on renal mercury
disposition and excretion in the rat.
Girardi G; El]ias MM
Facultad de Ciencias' Bioqu]imicas y Farmac]euticas' Universidad
Nacional de Rosario' Rep]ublica Argentina.
Toxicology, 81(1):57-67 1993 Jul 11
mercury renal disposition has been studied following HgCl2 inJection
(5.0 mg/kg body wt.' s.c.) in controls' diethylmaleate and
N-acetylcysteine-treated rats. The different treatments were used to
generate statistically different degrees of non-protein sulfhydryls
concentration in kidneys. Diethylmaleate (4 mmol/kg body wt.' i.p.)
diminished kidney glutathione levels to 25% and N-acetylcysteine (2
mmol/kg body wt.' i.p.) increased kidney non-protein sulfhydryls levels
up to 75% compared with new controls. The amount of mercury in the
kidneys' the mercury excretion rate in urine and the mercury plasma
disappearance curves were calculated during 3 h post HgCl2 inJection.
BUN was measured in plasma at the same time period to determine the
onset of kidney damage. The results indicate a higher HgCl2 renal
clearance in N-acetylcysteine-treated rats compared to controls and
less renal mercury accumulation. The data agree with diminished renal
toxicity. On the other hand' renal mercury accumulation was higher and
mercury renal clearance lower in diethylmaleate-treated animals'
associated with higher renal toxicity. The results suggest that
non-protein sulfhydryl levels (principally glutathione) might determine
renal accumulation of mercury as well as its elimination rate and hence
might enhance or mitigate the nephrotoxicity induced by the metal.

Renal glutathione and mercury uptake by kidney.
Berndt WO; Baggett JM; Blacker A; Houser M
Fundam Appl Toxicol, 5(5):832-9 1985 Oct
The kidney is well documented as the target organ for mercuric ion.
Mechanisms by which this ion accumulates in renal tissue, however, are
less well understood. Sulfhydryl groups in renal tissue might well bind
this metal and serve as a sink for its accumulation. Various studies
have indicated that both methyl mercury as well as mercuric ion are
accumulated less by renal tissue after depletion of nonprotein
sulfhydryl groups. A similar reduction in hepatic accumulation of
mercuric ion or methyl mercury does not occur after nonprotein
sulfhydryl depletion. This observation may relate to the higher tissue
content of nonprotein sulfhydryls in liver than kidney or to a
fundamentally different mechanism of metal uptake. Mercuric ion
accumulation by renal tissue also can be reduced by ureteral occlusion,
a reduction that is less than that for inulin in comparable
experiments. These data are complex and do not clearly establish a role
for filtration in the delivery of mercury to the kidney. Inhibition of
the renal enzyme gamma-glutamyl transpeptidase (gamma-GT) results in a
marked increase in the excretion of both glutathione and mercury in the
urine. Although there is a tendency for kidneys of the
gamma-GT-inhibited animals to contain less mercury than controls, the
change in renal content was not significant. These observations suggest
that gamma-GT may have a role in the reabsorption of mercury from the
tubular lumen. Interestingly, both mercuric chloride-induced mortality
and effects on renal slice accumulation of organic ions were enhanced
in the presence of nonprotein sulfhydryl depletion caused both by
immediate depletion of the glutathione pool and by inhibition of its

Role of glutathione and hepatic glutathione S-transferase in the
biliary excretion of methyl mercury, cadmium and zinc: a study with
enzyme inducers and glutathione depletors.
Gregus Z; Varga F
Acta Pharmacol Toxicol (Copenh), 56(5):398-403 1985 May
The effect of hepatic glutathione (GSH) depletion and enzyme induction
on hepatic glutathione S-transferase (GST) activity, biliary excretion
of GSH, methyl mercury, cadmium and zinc was studied in rats. The GSH
depletors, methyl iodide and diethyl maleate, did not influence hepatic
GST activity but, depending on the substrate used, benzo(a)pyrene,
phenobarbital, pregnenolone-16 alpha-carbonitrile (PCN) and
trans-stilbene oxide (TSO) increased it by 16-33, 44-89, 53-97 and
208-279%, respectively. GSH depletors decreased (-88%), benzo(a)pyrene
and TSO did not affect, phenobarbital and PCN increased (+113 and
+149%) the transport of GSH into bile. The biliary excretion of methyl
mercury, cadmium and zinc was reduced by GSH depletors (-97, -74 and
-93%), and enhanced by phenobarbital (+139, +280 and +220%) and PCN
(+150, +121 and +160%). Treatment with benzo(a)pyrene and TSO did not
affect the excretion of methyl mercury and zinc into bile, but
decreased that of cadmium. These results do not provide evidence for
the role of hepatic GST but strongly support the importance of biliary
GSH excretion in the hepatobiliary transport of methyl mercury, cadmium
and zinc. It is assumed that phenobarbital and PCN enhance the biliary
excretion of these metals by increasing the transport of GSH, the
carrier molecule, from liver to bile.

Accumulation and handling of inorganic mercury in the kidney after
coadministration with glutathione.
Zalups RK; Barfuss DW
Division of Basic Medical Sciences' Mercer University School of
Medicine' Macon' Georgia 31207' USA.
J Toxicol Environ Health, 44(4):385-99 1995 Apr
The accumulation and handling of mercury in the blood' kidneys' and
liver were evaluated and compared in rats 5 min' 1 h' and 24 h after
the intravenous administration of either a 0.25 mumol/kg dose of
inorganic mercury or a 0.25 mumol/kg dose of inorganic mercury plus a
0.5 mumol/kg dose of glutathione (GSH) to determine the possible role
of extracellular GSH and complexes of GSH and inorganic mercury in the
renal uptake and transport of inorganic mercury. Significantly more of
the inJected dose of inorganic mercury was present in the blood of the
rats inJected with inorganic mercury alone than in the blood of the
rats inJected simultaneously with both inorganic mercury and GSH at all
times evaluated after inJection. Of the mercury remaining in the blood'
however' significantly more mercury was in plasma fraction of blood in
the rats inJected with both inorganic mercury and GSH than in the
plasma fraction of blood in the rats inJected with inorganic mercury
alone. The blood and plasma findings indicate that much of the mercury
inJected with GSH was in some complex that allowed the mercury to be
cleared from the blood more readily and prevented the mercury from
entering readily into red blood cells. The renal concentration of
mercury was significantly greater in the rats inJected with both
inorganic mercury and GSH than in the rats inJected with inorganic
mercury alone at 5 min and 1 h' but not 24 h' after inJection. This
increased renal accumulation of mercury during the initial hours after
inJection was due mainly to enhanced uptake and/or retention of mercury
in the renal cortex. Urinary excretion of mercury' over 24 h' was also
slightly' but significantly' greater in the rats inJected with both
inorganic mercury and GSH simultaneously. These data indicate that
coadministration of a nontoxic dose of inorganic mercury with a twofold
higher amount (in moles) of GSH increases significantly the clearance
of mercury from the blood and increases the renal cortical accumulation
of inorganic mercury during the initial 1 h after inJection. Moreover'
the data in this study are consistent with the hypothesis that
extracellular GSH is an important ligand to which mercuric ions bind'
and that complexes of inorganic mercury and GSH in the blood and/or
ultrafiltrate probably play a role in the renal uptake of some of the
mercury in blood after exposure to mercuric compounds.

Effect of lipoic acid on biliary excretion of glutathione and metals.
Gregus Z; Stein AF; Varga F; Klaassen CD
Department of Pharmacology' University Medical School of P]ecs'
Toxicol Appl Pharmacol, 114(1):88-96 1992 May
Several metals are excreted in bile as glutathione complexes' and their
biliary excretion is facilitated by increased hepatobiliary transport
of glutathione. The present study analyzed the effect of lipoic acid
(LA; thioctic acid; 37.5-300 mumol/kg' iv)' an endogenous disulfide
which can be reduced in vivo to a dithiol' on the hepatobiliary
disposition of glutathione-related thiols and the biliary excretion of
metals (10 mumol/kg' iv) in rats. Administration of LA enhanced the
biliary excretion of reduced glutathione in a dose-dependent fashion.
Despite increasing glutathione output' LA (150 mumol/kg' iv) did not
increase' but rather decreased' the biliary excretion of methylmercury'
cadmium' zinc' and copper' which are transported into bile in a
glutathione-dependent manner' as indicated by a marked reduction in
their biliary excretion after diethyl maleate-induced glutathione
depletion. In contrast' biliary excretion of inorganic mercury' which
is minimally affected by glutathione depletion' was dramatically
enhanced (12- to 37-fold) by LA administration. Following inJection of
LA' the concentrations of endogenous disulfides in arterial blood
plasma (e.g.' cystine' glutathione disulfide' cysteine-glutathione'
protein-cysteine' and protein-glutathione mixed disulfides) were
considerably diminished' while the levels of endogenous thiols (e.g.'
glutathione and cysteine) were increased. This finding indicates that
LA' probably after enzymatic conversion to dihydrolipoic acid' can
reduce endogenous disulfides to thiols. It appears that LA induces the
transport of glutathione into bile by the temporary formation of
dihydrolipoic acid-glutathione mixed disulfide' which after being
translocated into bile is cleaved to LA and reduced glutathione.
Because the glutathione molecule thus transported into bile cannot
complex metals at the thiol group' this might be the mechanism for the
observed failure of the LA-induced increase in biliary excretion of
glutathione to enhance the hepatobiliary transport of metals that are
transported into bile as glutathione complexes (i.e.' methylmercury'
cadmium' zinc' and copper). The observations also raise the possibility
that endogenous dihydrolipoic acid' by forming a stable complex with
mercuric ion' may play the role of a carrier molecule in the
hepatobiliary transport of inorganic mercury.

Fluctuation of trace elements during methylmercury toxication and
chelation therapy.
Bapu C; Purohit RC; Sood PP
Department of Biosciences' Saurashtra University' RaJkot' India.
Hum Exp Toxicol, 13(12):815-23 1994 Dec
The aim of the present investigation was to check the fluctuation in
essential elements' such as Na' K' Mg' Mn' Cu' Zn' Cr and Ni in the
brain' spinal cord' liver and kidney of mice during methylmercury
chloride (MMC) toxication and therapy with monothiols
(N-acetyl-DL-homocysteine thiolactone and glutathione) and vitamins
(vitamin B complex and E). mercury deposition and its elimination
during chelation therapy were also screened for comparative purposes.
The animals were dosed for 7 days with MMC 1 mg/kg/d and some were then
kept without treatment for a further. 7 days. Other MMC-treated animals
were immediately given one of the above antidotes for 7 days. All the
animals were sacrificed on the 15th day. There was a decrease in all
elements during MMC toxication with few exceptions' for example' copper
was increased in the liver as was sodium in the kidney. Treatment with
the thiols and vitamins restored the levels of these elements in
certain tissues towards normal' but their concentrations remained
abnormal in most instances. The fluctuations in the concentration of
these elements were attributed to their association with various

Biliary secretion of glutathione and of glutathione-metal complexes.
Ballatori N; Clarkson TW
Fundam Appl Toxicol, 5(5):816-31 1985 Oct
As bile is the main route of elimination of many metals, a large number
of studies have been directed toward the characterization of the
hepatobiliary transport of both endogenous and exogenous metals.
Although some progress has been made, we still know little of the basic
mechanisms involved in the hepatocellular uptake of metals, in their
intracellular translocation and metabolism, or in their transport into
bile. Our recent studies have focused on the last step in the
hepatobiliary transport of mercury, namely, the secretion of the metal
from liver cells into bile. The rate of secretion of methyl and
inorganic mercury into bile was low in suckling rats and rapidly
increased to adult rates soon after weaning. These changes closely
followed similar developmental changes in the biliary secretion of
reduced glutathione (GSH). When GSH secretion into bile was completely
inhibited, without changing hepatic levels of GSH or mercury, mercury
secretion was also completely blocked. mercury secretion paralleled
individual and sex-related differences in GSH secretion. At the same
time, the secretion of mercury was independent of bile flow, of the
thiol and mercury concentration gradients between bile and liver cells,
and of those between bile and plasma. Our results, therefore, indicate
a close coupling between the secretion of mercury and that of GSH.
These in vivo findings, along with in vitro studies by others in
vesicles isolated from the canalicular membrane of the liver cell,
indicate a carrier-mediated transport system for GSH, but the nature of
the linkage of this transport system with mercury secretion is not yet
fully established. Our data and those in the literature are consistent
with the involvement of at least two steps in the movement of mercury
from liver cells to bile--the formation of a mercury-glutathione
complex in the liver cell, followed by the secretion of this complex
through a process closely linked to GSH secretion. The identification
of GSH as an endogenous complexing agent in the transport of metals
between tissues and body fluids now permits the design of therapeutic
strategies aimed at exploiting this transport vehicle to effect the
removal of metals via physiological routes of excretion. The present
discussion considers the role of GSH in the hepatobiliary transport of
metals. In doing so, a brief review is given of current understanding
of hepatic GSH metabolism and transport.

Effect of sex hormones on the fate of methylmercury and on glutathione
metabolism in mice.
Hirayama K; Yasutake A; Inoue M
Biochem Pharmacol, 36(12):1919-24 1987 Jun 15
To investigate the mechanisms for the sex-related difference in the in
vivo fate of methylmercury (MeHg), the effects of hormonal manipulation
on the distribution and urinary excretion of the mercurial moiety (Hg)
of injected MeHg and on hepato-renal metabolism of glutathione were
studied in C57BL/6N mice. Twenty-four hours after oral administration
of MeHg, urinary Hg levels were significantly higher in males than in
females. Tissue Hg levels of males were higher in the kidney, but lower
in the brain, liver and plasma than those of females. The fate of
injected MeHg in castrated males was similar to that in normal females
except for its brain levels. This feminization of the mercurial
behavior in the castrated males was restored by treating with
testosterone propionate (TP). When control mice were treated with TP,
urinary excretion of Hg increased in both sexes, whereas renal Hg level
increased only in females. Administration of estradiol benzoate (EB) to
males decreased the renal accumulation and urinary excretion of Hg,
whereas its hepatic levels increased. However, no significant change in
the fate of MeHg was found in females pretreated with EB. Castration of
females slightly decreased the urinary excretion of Hg. Thus, tissue
distribution and urinary excretion of the administered MeHg seem to be
subject to sex hormone control. Since MeHg has a high affinity for GSH,
effects of hormonal manipulation on the metabolism of hepato-renal
glutathione were also investigated. A significant sex-related
difference in glutathione levels was found in plasma but not in the
kidney, liver and erythrocytes. The half-lives of glutathione in the
liver and kidney were significantly shorter in males than in females as
determined by treatment with buthionine sulfoximine, a specific
inhibitor of GSH synthesis. This difference was also modulated by the
hormonal treatment. Since half-lives of GSH in the liver and kidney
predominantly reflect the rate of its efflux from these tissues, the
results suggest that GSH metabolism and/or secretory transport may be
regulated by sex hormones. These and other observations suggest that
the fate of MeHg may be modulated by way of regulating the inter-organ
metabolism and transport of glutathione and its derivatives.

Analysis of protective activity of N-acetylcysteine against
teratogenicity of heavy metals.
Endo A; Watanabe T
Department of Hygiene and Preventive Medicine, Yamagata University
School of Medicine, Japan.
Reprod Toxicol, 2(2):141-4 1988
N-acetylcysteine (NAC) is known to enhance the renal excretion of heavy
metals. Therefore, we investigated whether the teratogenicity of metals
(Hg, Cr, and Cd) can be ameliorated by NAC in mice. Contrary to our
expectation, the incidence of congenital malformations produced by
these metals was two to three times higher in the mice that were fed
NAC (0.2% in the diet). The underlying mechanism or mechanisms are
unknown and should be investigated.

Effects of exercise training on the distribution of metallic mercury in
ShimoJo N; Arai Y
Institute of Community Medicine' University of Tsukuba' Ibaraki' Japan.
Hum Exp Toxicol, 13(8):524-8 1994 Aug
1. The purpose of this study was to correlate exercise induced changes
of antioxidant enzymes with the distribution of mercury after mercury
vapour exposure in mice. 2. Exercise training consisted of swimming (1
h/day for 5 days/week) for 9 weeks. After 9 weeks of training'
swim-trained mice showed significantly elevated levels of catalase
(CAT)' superoxide dismutase (SOD) and glutathione peroxidase (GSHpx) in
their red blood cells' CAT and GSHpx in their kidneys and SOD in the
liver. 3. Exercised mice (Ex) and non-exercised mice (N.Ex) were
exposed to mercury vapour (3.5 mg m-3) for 1 h. mercury concentrations
were assayed in the blood' brain' heart' lungs' liver and kidneys along
with the mercury content of the entire body. The whole body mercury
content showed no significant difference in any measurement
(immediately' 24 h and 48 h after mercury exposure) between the Ex and
N.Ex groups. mercury concentrations in the Ex group were significantly
higher than the N.Ex group in the heart' whole blood' red blood cells
and the brain at 24 and 48 h; and in the plasma and kidneys at 24 h. 4.
It was concluded that exercise training is a factor in distribution
changes of mercury after exposure to mercury vapour' though it is not a
factor in the total absorption and excretion of mercury.


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