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Title
Dose and duration related methylmercury deposition' glycosidases
inhibition' myelin degeneration and chelation therapy.
Author
Vinay SD; Raghu KG; Sood PP
Address
Department of Biosciences' Saurashtra University' RaJkot' India.
Source
Cell Mol Biol, 36(5):609-23 1990
Abstract
Methylmercury accumulation in different parts of the CNS (olfactory
bulbs' cerebral hemispheres' cerebellum' medulla oblongata and
spinal
cord) in relation to the cytoarchitectural changes in myelin
sheath as
well as in glycosidases levels have been reported. Male albino
rats
were treated with low and high doses of methylmercury chloride
(1 mg/kg
and 10 mg/kg) N-acetyl-DL-homocysteine thiolactone (40 mg/kg
and 80
mg/kg) and glutathione (100 mg/kg and 150 mg/kg) for varied time
periods. The study shows a dose and duration dependent accumulation
of
mercury in all the CNS areas coinciding with a progressive myelin
degeneration and inhibition of the glycosidases. A casual relationship
between the amount of mercury accumulation and the extent of
enzymes
inhibition' in any particular area of CNS' could not be established.
Similarly none of the antagonists is (though has been successful
in
recovering the enzymes and lessening the mercury burden in a
few
isolated cases) able to bring an absolute control value in any
group.
Title
glutathione monoethyl ester moderates mercuric chloride-induced
acute
renal failure.
Author
Houser MT; Milner LS; Kolbeck PC; Wei SH; Stohs SJ
Address
Department of Pediatrics' University of Nebraska Medical Center'
Omaha
68198-2165.
Source
Nephron, 61(4):449-55 1992
Abstract
glutathione (GSH)-dependent reactions are an important cellular
defense
against ischemic or oxidative inJury' although their role in
toxin-induced renal cellular inJury is less clear. Because of
the known
sulfhydryl reactivity of mercury (M)' we hypothesized that GSH
could
modify mercuric chloride (MC)-induced acute renal failure (ARF).
Therefore' we evaluated the effects of glutathione monoethyl
ester
(GE)' which produces high intrarenal levels of GSH' on the
nephrotoxicity of MC. GE treatment in normal rats did not alter
their
creatinine clearance (CCr)' fractional sodium (CNa/CCr) or lysozyme
(CLy/CCr) excretion' but histologically resulted in prominent
proximal
tubular vacuolization. GE pretreatment in rats with MC-induced
ARF
resulted in partial preservation of their CCr' CNa/CCr and CLy/CCr.
Renal histology also demonstrated a reduction in tubular necrosis.
M
content in the renal cortex 3 following MC was lower in the MC
+ GE
group' but levels were higher in the liver and inner stripe/inner
medulla as compared to animals receiving MC alone. No differences
were
seen in the outer stripe at 3 h or in any of the tissues 24 h
following
MC inJection. Thus' GE moderated MC-induced ARF' likely by providing
a
large intracellular sulfhydryl pool and thereby reducing M reactivity
with endogenous cellular proteins and enzymes.
Title
Ameliorative capacities of vitamins and monothiols post therapy
in the
restoration of methylmercury altered glutathione metabolism.
Author
ViJayalakshmi K; Sood PP
Address
Department of Biosciences' Saurashtra University' RaJkot' India.
Source
Cell Mol Biol (Noisy-le-grand), 40(2):211-24 1994 Mar
Abstract
The recovery of glutathione and its metabolising enzymes (glutathione
disulfide reductase' glutathione peroxidase' thiol transferase'
gamma-glutamyl transpeptidase and glutathione transferase) along
with
sulfhydryl groups and byproduct of lipid peroxidation (malondialdehyde)
in the brain' spinal cord' kidney and liver of mice' altered
during
methylmercury chloride (MMC) intoxication' is recorded in
post-therapeutic treatment with vitamins and monothiols. For
this
purpose ten groups of animals were intoxicated with 1 mg/kg MMC/day
for
7 days. Out of these' one group was sacrificed on 8th day and
one group
was kept without toxicant for another seven days before sacrificing
on
15th day. Study shows significant decrease of various biomolecules
of
glutathione metabolism during MMC application' which are further
decreased with increasing the duration on 15th day. The trend
is same
in all the tissues with few exceptions. However' malondialdehyde'
a
byproduct of lipid peroxidation' is increased with increasing
the
duration after intoxication. Study also shows a significant recovery
(in many cases a complete control level) of most of the components
with
one or the other chelator or with their combined therapy. Therefore'
it
is concluded from overall study that vitamins B complex and E'
GSH (or
its precursor NAHT) either alone or in combinations' are quite
suitable
for methylmercury post-therapy.
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
Redox activities of mercury-thiol complexes: implications for
mercury-induced porphyria and toxicity.
Author
Miller DM; Woods JS
Address
Department of Environmental Health' School of Public Health and
Community Medicine' University of Washington' Seattle 98195.
Source
Chem Biol Interact, 88(1):23-35 1993 Jul
Abstract
mercury exposure causes oxidative damage to the kidney' resulting
in
numerous biochemical changes' including the excretion of excess
porphyrins in the urine (porphyrinuria). Hg(II)-induced porphyrinuria
may occur' in part' by the previously reported oxidation of reduced
porphyrins (porphyrinogens) by a GSH/Hg(II) complex and H2O2.
To
further elucidate the mechanism(s) of porphyrinogen oxidation
by GSH'
Hg(II)' and H2O2' we compared the ability of several thiol compounds
and peroxides to substitute for GSH or H2O2' respectively' in
the
oxidation of uroporphyrinogen (urogen). Every thiol compound
tested
resulted in enhanced urogen oxidation in the presence of Hg(II)
and
H2O2' albeit at different rates. Additionally' t-butyl or cumene
hydroperoxide substituted for H2O2 in promoting urogen oxidation'
although neither peroxide was as effective in this regard.
mercury-thiol complexes synthesized from Hg(I) and GSSG also
promoted
urogen oxidation in the presence of H2O2. Additionally' in the
absence
of urogen' both GSH/Hg(II) or GSSG/Hg(I) catalyzed the decomposition
of
H2O2. Finally' incubation of GSH/Hg(II) or GSSG/Hg(I) with H2O2
resulted in HPLC-detectable products distinct from GSH' GSSG'
or
GS2Hg(II). These findings suggest that mercury-thiol complexes
possess
redox activity in biological systems' which promotes the oxidation
of
porphyrinogens and possibly other biomolecules.
Title
Effects of sulfhydryl compounds on the accumulation' removal
and
cytotoxicity of inorganic mercury by primary cultures of rat
renal
cortical epithelial cells.
Author
Endo T; Sakata M
Address
Faculty of Pharmaceutical Sciences' Health Sciences University
of
Hokkaido' Japan.
Source
Pharmacol Toxicol, 76(3):190-5 1995 Mar
Abstract
The effects of sulfhydryl compounds on the accumulation' removal
and
cytotoxicity of inorganic mercury (Hg) were investigated in primary
cultures of rat renal cortical epithelial cells. The compounds
investigated were 2'3-dimercaptosuccinic acid'
2'3-dimercapto-1-propanol' D-penicillamine' glutathione (GSH)
and
L-cysteine. In the accumulation experiment' the cells were co-incubated
with Hg and the above compounds for 30 min. (short-term) or 18
hr
(long-term). In the removal experiment' cells incubated with
Hg were
further incubated with the above compounds for 30 min. In both
experiments' the alleviative effect of the compounds on the
cytotoxicity was estimated by the uptake of neutral red or by
cell
growth. 2'3-Dimercaptosuccinic acid had the highest antidotal
effects
except for Hg removal. 2'3-Dimercapto-1-propanol exerted the
least
antidotal effects in the short-term' as well as in the long-term
experiments' 2'3-dimercapto-1-propanol increased the Hg accumulation
and the cytotoxicity despite its removal of most of the Hg. Although
D-penicillamine' L-cysteine and GSH did not increase the Hg removal
in
the long-term experiment other antidotal effects were seen.
Title
In vivo renal tubular secretion and metabolism of the disulfide
of
2,3-dimercaptopropane-1-sulfonate.
Author
Stewart JR; Diamond GL
Address
Dept. of Pharmacology, University of Rochester School of Medicine
and
Dentistry, NY 14642.
Source
Drug Metab Dispos, 16(2):189-95 1988 Mar-Apr
Abstract
The in vivo renal tubular secretion and metabolism of the disulfide
of
the heavy metal-complexing agent 2,3-dimercaptopropane-1-sulfonate
(DMPS) was examined in the Sperber preparation. DMPS was readily
oxidized to DMPS disulfide when incubated with chicken plasma,
with
whole blood or with urine in the presence of transition metals.
Net
reduction of the disulfide was not detected when the disulfide
was
incubated with chicken blood. When the disulfide was infused
into the
saphenous vein of chickens at a rate of 1 mumol of DMPS
equivalents.min-1.kg of body weight-1, 62% of the DMPS disulfide
that
entered the renal portal circulation of the ipsilateral kidney
was
excreted in the urine unchanged during a single pass through
the
peritubular capillaries, 28% was excreted as DMPS, and 9% as
an
unidentified mixed disulfide. Net reduction of DMPS disulfide
to DMPS
occurred in vitro in rat kidney cytosol (pH 7.4) supplemented
with 0.5
or 5.0 mM reduced glutathione. Reduction of DMPS disulfide to
DMPS also
occurred in EDTA-Tris HCl (pH 9) containing glutathione disulfide
and
glutathione reductase. Intracellular reduction of DMPS disulfide
to
DMPS in the kidney, involving a glutathione-disulfide exchange
reaction, may be important for the in vivo activity of DMPS as
a
complexing agent for mercury.
Title
Species differences in biliary excretion of methylmercury--role
of
non-protein sulfhydryls in bile.
Author
Urano T; Naganuma A; Imura N
Address
Department of Public Health, School of Pharmaceutical Sciences,
Kitasato University, Tokyo, Japan.
Source
Res Commun Chem Pathol Pharmacol, 62(2):339-51 1988 Nov
Abstract
Species differences in biliary excretion of methylmercury and
non-protein sulfhydryls (NPSHs) were studied using male rats,
mice,
rabbits, guinea pigs and hamsters. EDTA was added to all mixtures
used
throughout the experimental procedures to prevent oxidation of
NPSHs.
The rates of mercury excretion into the bile of guinea pigs and
rabbits
after the administration of methylmercury were significantly
lower than
those in rats, mice and hamsters. Total NPSH concentrations in
the bile
of guinea pigs and rabbits analyzed by HPLC were also relatively
low
compared with those in the other species. These results suggested
that
NPSH excretion plays an important role in species differences
of
methylmercury excretion into bile. The chemical form of the
methylmercury in the bile was analyzed by gel filtration with
Sephadex
G-15, and most of methylmercury in bile of all species used in
the
experiment was bound to low molecular weight substances. The
main form
of methylmercury in the bile was methylmercury-glutathione (MM-GSH)
in
mice and hamsters and methylmercury-cysteinylglycine (MM-CysGly)
in
guinea pigs. Methylmercury in the bile of mice, hamsters and
guinea
pigs was associated with the main component of NPSHs in bile
of the
respective species. In the rat bile, however, GSH accounted for
a
majority (80%) of NPSHs, but methylmercury was separated in two
peaks
on gel filtration, i.e. MM-CysGly (70%) and MM-GSH (30%). This
may be
explained by the higher affinity of CysGly to methylmercury than
that
of GSH. Our data indicate that species differences in the chemical
forms of biliary methylmercury reflect the species differences
in NPSH
components in the bile.
Title
Toxic heavy metal ions activate the heme-regulated eukaryotic
initiation factor-2 alpha kinase by inhibiting the capacity of
hemin-supplemented reticulocyte lysates to reduce disulfide bonds.
Author
Matts RL; Schatz JR; Hurst R; Kagen R
Address
Department of Biochemistry' Oklahoma State University' Stillwater
74078-0454.
Source
J Biol Chem, 266(19):12695-702 1991 Jul 5
Abstract
Addition of toxic heavy metal ions (Cd2+' Hg2+' and Pb2+) to
hemin-supplemented rabbit reticulocyte lysate brings about the
activation of the heme-regulated eukaryotic initiation factor
2 alpha
kinase (HRI) and the inhibition of protein chain initiation.
In this
report we examined the effects of monothiol and dithiol compounds'
metal ion-chelating agents' and metallothioneins (MT) on metal
ion-induced inhibition of protein synthesis. The dithiol compounds
dithiothreitol and 2'3-dimercaptopropane sulfonic acid prevented
and
relieved the inhibition of protein synthesis caused by Cd2+ and
Hg2+ in
hemin-supplemented lysates' but the monothiol compounds
2-mercaptoethanol' cysteamine' D-(-)penicillamine' and glutathione
had
no effect. The inhibition of protein synthesis caused by Cd2+
was
reversed by the addition of excess EDTA but not by the addition
of
excess nitrilotriacetic acid. Toxic heavy metal ions inhibited
the
capacity of hemin-supplemented lysate to reduce disulfide bonds.
Addition of excess EDTA to Cd(2+)-inhibited lysates restored
the
capacity of the lysate to reduce disulfide bonds and inhibited
the
phosphorylation of eukaryotic initiation factor eIF-2. MTs and
their
apoproteins (apoMTs) inhibited the activation of HRI and protected
protein synthesis from inhibition by Cd2+' Hg2+' and Pb2+. Addition
of
apoMTs to heavy metal ion-inhibited lysates restored the capacity
of
lysates to reduce disulfide bonds. The restoration of the lysate`s
thioredoxin/thioredoxin reductase activity was accompanied by
the
inactivation of HRI and the resumption of protein synthesis'
indicating
that apoMTs can "detoxify metal ions already bound to proteins.
Several
observations presented in this report suggest that the binding
of metal
ions to the alpha-domain of MT is responsible for the ability
of MT to
sequester bound metal in a non-toxic form. Addition of glucose
6-phosphate or NADPH had no effect on protein synthesis in metal
ion-inhibited lysates' and NADPH concentrations in Cd(2+)-inhibited
and
hemin-supplemented control lysates were equivalent. The data
suggest
that the metal ions cause the inhibition of protein synthesis
by
binding to vicinal sulfhydryl groups present in some critical
protein(s)' possibly the dithiols present in the active site
of
thioredoxin and (or) thioredoxin reductase' which leads to the
activation of HRI. |
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