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Title
Organ distribution and cellular uptake of methyl mercury in the
rat as
influenced by the intra- and extracellular glutathione concentration.
Author
Alexander J; Aaseth J
Source
Biochem Pharmacol, 31(5):685-90 1982 Mar 1
Abstract
Intravenous administration of CH3HgCl (4 mumol/Kg) premixed with
glutathione or cysteine (8 mumole/kg) to female rats caused a
rapid
uptake of mercury in the kidney and a depressed content in the
liver
and blood as compared to CH3HgCl given alone. GSH depletion in
the
tissues, produced by injection of diethylmaleate, DEM (3.9 mmole/kg)
did not influence the kidney uptake of mercury from administered
(CH3Hg+-GSH, whereas the uptake of injected CH3HgCl was depressed.
Both
GSH and cysteine (8 mumole/kg) promoted the biliary excretion
of methyl
mercury. In suspensions of rat erythrocytes and isolated hepatocytes,
additions of GSH reduced the cellular uptake of CH3Hg+ from the
medium,
whereas this was increased in the hepatocytes by adding cysteine
or
methionine. cysteine addition slightly reduced the uptake of
CH3Hg+ in
the erythrocytes. GSH-depletion as obtained by DEM pretreatment
of the
cells, reduced the Ch3Hg+ uptake into hepatocytes by 40%, in
contrast
to only a negligible effect on the erythrocytes. Our results
support
previous reports that a physiological CH3Hg+-GSH-complexation
takes
place intracellularly, at least in liver cells. Our results are
furthermore consistent with the assumption that biliary excreted
CH3Hg+-GSH, which can be reabsorbed, only to a limited extent
is taken
up by the liver, whereas this GSH-complexation and reabsorption
is of
importance for the Ch3Hg+-uptake in the kidneys.
Title
The effect of oral doses of a polythiol resin on the excretion
of
methylmercury in mice treated with cysteine, D-penicillamine
or
phenobarbitone.
Author
Magos L; Clarkson TW
Source
Chem Biol Interact, 14(3-4):325-35 1976 Aug
Abstract
Mice dosed with methylmercury chloride (0.5 to 2.0 mg Hg/kg i.p.)
labeled with the 203Hg isotope were given polythiol resin in
their food
(2% w/w). The effect of pretreatment with phenobarbitone, or
co-administration of D-penicillamine or L-cysteine, was tested
on the
efficacy of the resin to accelerate the excretion of methylmercury.
The
effect of the polythiol resin in enhancing fecal excretion was
dependent on the dose of methylmercury, it being significantly
greater
at doses of 1.0 and 2.0 than at 0.5 mg Hg/kg. In animals given
the
resin and phenobarbitone (0.1% w/w drinking water), fecal excretion
was
approx. 36% greater than in animals given resin alone. Penicillamine
(2.5 mg/ml drinking water) actually retarted elimination of
methylmercury in animals given the resin. Despite the enhanced
efficacy
of the resin plus phenobarbitone, the brain levels of methylmercury
were not reduced beyond those seen in animals given resin alone.
The
mechanisms and implications of these effects are discussed.
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
Toxicity, distribution, and elimination of thiol complexes of
methylmercury after intracerebral injection.
Author
Fair PH; Balthrop JE; Wade JL; Braddon-Galloway S
Source
J Toxicol Environ Health, 19(2):219-33 1986
Abstract
Intracerebral injection of CH3Hg and CH3Hg complexed with glutathione
(GSH), cysteine (cys), cysteinylglycine (cys-gly), and homocysteine
(homocys) resulted in differences in toxicity. Criteria based
on
neurological indices, mortality, and weight loss indicated that
the
cys-gly complex of CH3Hg was significantly less toxic than CH3Hg
or the
other complexes. The other complexes of CH3Hg (GSH, homocys,
and cys)
were also found to be less toxic than CH3Hg. The selenium status
of the
animal did not seem to significantly influence the toxicity of
CH3Hg
and the complexes. While CH3Hg complexed to cys-gly was significantly
less toxic than CH3Hg alone, there were no differences observed
in the
CH3Hg half-life values or in the distribution of these compounds
in the
kidneys, brain, liver, and blood. It was observed, however, that
the
CH3Hg--cys-gly complex had higher fecal excretion on d 3 and
4
following intracerebral injection.
Title
Tubular secretion and reabsorption of mercury compounds in mouse
kidney.
Author
Tanaka-Kagawa T; Naganuma A; Imura N
Address
Department of Public Health, School of Pharmaceutical Sciences,
Kitasato University, Tokyo, Japan.
Source
J Pharmacol Exp Ther, 264(2):776-82 1993 Feb
Abstract
To determine whether Hg accumulated in renal cells is secreted
into the
lumen of proximal tubules with intracellular glutathione (GSH)
and
reabsorbed by tubular cells via a gamma-glutamyltranspeptidase
(gamma-GTP)-dependent process as in the case of GSH itself, the
effect
of postadministration of acivicin (1 mmol/kg i.p.), a gamma-GTP
inhibitor, on renal Hg accumulation was investigated in mice.
Renal Hg
content 4 hr after injection of CH3HgCl or HgCl2 (5 mumol/kg
i.v.) was
decreased to 35 or 44% of control, respectively, but urinary
Hg
excretion was increased by acivicin administration 2 hr after
injection
of the mercurials. When renal GSH was decreased to 19% of control
by
treatment with DL-buthionine-S,R-sulfoximine (4 mmol/kg s.c.)
2 hr
before acivicin injection, the increase in urinary Hg excretion
caused
by acivicin was suppressed. Acivicin administration 24 hr after
injection of the mercurials decreased renal methylmercury content
determined 2 hr after acivicin injection and increased urinary
Hg
excretion. The postadministration of acivicin, however, did not
affect
the renal content of inorganic Hg which predominantly bound to
metallothionein (MT) induced by HgCl2 itself. Pretreatment with
Bi(NO3)3 as a renal MT inducer diminished the effect of acivicin
administered 2 hr after HgCl2 injection on renal Hg content and
urinary
excretion. These results suggest that methylmercury and inorganic
Hg
bound to ligands other than MT in renal cytosol may be secreted
into
the lumen of proximal tubules with intracellular GSH and be reabsorbed
via a gamma-GTP-dependent process.
Title
Possible role of hepatic glutathione in transport of methylmercury
into
mouse kidney.
Author
Naganuma A; Oda-Urano N; Tanaka T; Imura N
Address
Department of Public Health, School of Pharmaceutical Sciences,
Kitasato University, Tokyo, Japan.
Source
Biochem Pharmacol, 37(2):291-6 1988 Jan 15
Abstract
The mechanism of the renal uptake of methylmercury was studied
in mice.
Preadministration of 1,2-dichloro-4-nitrobenzene (DCNB), which
is a
reagent that depletes hepatic glutathione (GSH) without affecting
the
renal GSH level, 30 min before injection of methylmercury significantly
decreased the renal accumulation of mercury. The renal accumulation
of
mercury in mice receiving methylmercury-GSH intravenously was
significantly higher than that in mice receiving methylmercuric
chloride. These results suggest the possibility that hepatic
GSH, as a
source of extracellular GSH, plays an important role in the renal
accumulation of methylmercury. No significant difference in renal
mercury accumulation between bile duct-cannulated mice and normal
mice
was observed, indicating that the enterohepatic circulation of
methylmercury is not an important factor in the renal accumulation
of
methylmercury in mice. Pretreatment of mice with acivicin, a
potent
inhibitor of gamma-glutamyl transpeptidase (gamma-GTP), significantly
depressed the renal uptake of methylmercury and increased the
urinary
excretion of GSH and methylmercury. In in vitro reactions,
methylmercury-GSH was degraded into methylmercury-cysteinylglycine
by
gamma-GTP, and this product was then converted to
methylmercury-cysteine by dipeptidase. These results suggest
that
methylmercury is transported into the kidney as a complex with
GSH, and
then incorporated into the renal cells after degradation of the
GSH
moiety by gamma-GTP and dipeptidase, although the methylmercury
bound
to extracellular GSH can be reversibly transferred to plasma
proteins
in the bloodstream.
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
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
Species difference in biliary excretion of methylmercury.
Author
Naganuma A; Imura N
Source
Biochem Pharmacol, 33(4):679-82 1984 Feb 15
Abstract
Species difference in the biliary excretion of methylmercury
was
studied in male rats, mice, rabbits and guinea pigs. The rates
of
mercury excretion (% dose/2 hr) into the bile of the rats, mice,
rabbits and guinea pigs during the 2 hr from 2 to 4 hr after
the
administration of methylmercury were 0.61, 0.091, 0.036 and 0.019,
respectively. These results suggest that biliary excretion and
enterohepatic circulation of methylmercury in the latter three
species
may not influence the fate of this compound as significantly
as in
rats. Most of the methylmercury excreted into the bile of rats
was
bound to glutathione (GSH). In the mouse bile, 40% of the methylmercury
was bound to GSH and the rest was found in a fraction eluted
at the
void volume of the Sephadex G-15 column. However, in the case
of the
rabbits and guinea pigs, methylmercury-GSH was scarcely detectable
in
the bile and almost all of the methylmercury was eluted at the
void
volume of the column.
Title
N-acetylpenicillamine potentiated excretion of methyl mercury
in rat
bile: influence of S-methylcysteine.
Author
Refsvik T
Source
Acta Pharmacol Toxicol (Copenh), 55(2):121-5 1984 Aug
Abstract
N-acetylpenicillamine, 5 mmol/kg body weight increased biliary
excretion of methyl mercury more than three fold. Upon simultaneous
administration of the same dose of N-acetylpenicillamine and
2,5
mmol/kg body weight of S-methylcysteine biliary excretion of
methyl
mercury increased only 1.5 fold. In both cases biliary sulfhydryl
concentration increased to the same extent, about 5 fold. Decreased
biliary excretion of methyl mercury, as a result of liver depletion
of
reduced glutathione by cyclohexene oxide, could be restored by
N-acetylpenicillamine. This restoration could be depressed by
S-methylcysteine. The experiments undertaken indicate that
N-acetylpenicillamine potentiated methyl mercury excretion occurs
by a
glutathione S-transferase dependent mechanism. Bile, collected
after
successive administration of methyl mercuric chloride, cyclohexene
oxide, S-methylcysteine and N-acetylpenicillamine contained the
methyl
mercuric derivatives of N-acetylpenicillamine and glutathione
together
with other methyl mercury carrying components not present in
control
bile. Whether these components play any role in the mechanism
of
N-acetylpenicillamine potentiated methyl mercury excretion cannot
be
stated from the present investigation. |
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