|
Title
Chelation in metal intoxication. XXVIII: Effect of thiochelators
on
mercury (II) toxicity: pre- and post treatment.
Author
Khandelwal S; Kachru DN; Tandon SK
Address
Industrial Toxicology Research Centre, Lucknow, India.
Source
Biochem Int, 16(5):869-78 1988 May
Abstract
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.
Title
Involvement of glutathione in the enhanced renal excretion of
methyl
mercury in CFW Swiss mice.
Author
Mulder KM; Kostyniak PJ
Source
Toxicol Appl Pharmacol, 78(3):451-7 1985 May
Abstract
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.
Title
Effect of different renal glutathione levels on renal mercury
disposition and excretion in the rat.
Author
Girardi G; El]ias MM
Address
Facultad de Ciencias' Bioqu]imicas y Farmac]euticas' Universidad
Nacional de Rosario' Rep]ublica Argentina.
Source
Toxicology, 81(1):57-67 1993 Jul 11
Abstract
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.
Title
Renal glutathione and mercury uptake by kidney.
Author
Berndt WO; Baggett JM; Blacker A; Houser M
Source
Fundam Appl Toxicol, 5(5):832-9 1985 Oct
Abstract
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
synthesis.
Title
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.
Author
Gregus Z; Varga F
Source
Acta Pharmacol Toxicol (Copenh), 56(5):398-403 1985 May
Abstract
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.
Title
Accumulation and handling of inorganic mercury in the kidney
after
coadministration with glutathione.
Author
Zalups RK; Barfuss DW
Address
Division of Basic Medical Sciences' Mercer University School
of
Medicine' Macon' Georgia 31207' USA.
Source
J Toxicol Environ Health, 44(4):385-99 1995 Apr
Abstract
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.
Title
Effect of lipoic acid on biliary excretion of glutathione and
metals.
Author
Gregus Z; Stein AF; Varga F; Klaassen CD
Address
Department of Pharmacology' University Medical School of P]ecs'
Hungary.
Source
Toxicol Appl Pharmacol, 114(1):88-96 1992 May
Abstract
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.
Title
Fluctuation of trace elements during methylmercury toxication
and
chelation therapy.
Author
Bapu C; Purohit RC; Sood PP
Address
Department of Biosciences' Saurashtra University' RaJkot' India.
Source
Hum Exp Toxicol, 13(12):815-23 1994 Dec
Abstract
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
macromolecules.
Title
Biliary secretion of glutathione and of glutathione-metal complexes.
Author
Ballatori N; Clarkson TW
Source
Fundam Appl Toxicol, 5(5):816-31 1985 Oct
Abstract
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.
Title
Effect of sex hormones on the fate of methylmercury and on glutathione
metabolism in mice.
Author
Hirayama K; Yasutake A; Inoue M
Source
Biochem Pharmacol, 36(12):1919-24 1987 Jun 15
Abstract
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.
Title
Analysis of protective activity of N-acetylcysteine against
teratogenicity of heavy metals.
Author
Endo A; Watanabe T
Address
Department of Hygiene and Preventive Medicine, Yamagata University
School of Medicine, Japan.
Source
Reprod Toxicol, 2(2):141-4 1988
Abstract
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.
Title
Effects of exercise training on the distribution of metallic
mercury in
mice.
Author
ShimoJo N; Arai Y
Address
Institute of Community Medicine' University of Tsukuba' Ibaraki'
Japan.
Source
Hum Exp Toxicol, 13(8):524-8 1994 Aug
Abstract
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. |
|
Return to Main Page
