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Title
Developmental changes in the biliary excretion of methylmercury
and
glutathione.
Author
Ballatori N; Clarkson TW
Source
Science, 216(4541):61-3 1982 Apr 2
Abstract
The long half-time for methylmercury in the neonatal rats is
explained
by the neonatal liver's inability to secrete the toxin into bile,
which
in adults is the main route of elimination. The ability to secrete
mercury into bile develops between 2 and 4 weeks of age and is
correlated with the increasing ability of the developing liver
to
secrete glutathione into bile.
Title
Physiological model for the pharmacokinetics of methyl mercury
in the
growing rat.
Author
Farris FF; Dedrick RL; Allen PV; Smith JC
Address
Division of Clinical Pharmacology, Center for Drug Evaluation
and
Research, Food and Drug Administration, Rockville, Maryland 20850.
Source
Toxicol Appl Pharmacol, 119(1):74-90 1993 Mar
Abstract
We describe a physiological pharmacokinetic model for methyl
mercury
and its metabolite mercuric mercury in the growing rat. Demethylation
appears to occur in both host tissues and gastrointestinal flora
with
elimination dominated by biliary secretion of inorganic mercury
and by
transport of methyl mercury into the gut lumen followed by substantial
bacterial metabolism. Biliary transport of both organic and inorganic
mercury is modeled in terms of the known secretion of glutathione
from
the hepatic pool. At 98 days following an oral tracer dose of
203Hg-labeled methyl mercury chloride, 65% of the administered
dose had
been recovered in the feces as inorganic mercury and 15% as organic
mercury. Urinary excretion is a minor elimination route, accounting
for
less than 4% of the dose as methyl mercury and 1% of the dose
as
inorganic mercury. Irreversible incorporation of the mercurials
into
hair is a significant route of elimination. Ten percent of the
administered dose was contained in the hair shed during the 98
days and
over 12% of the dose (almost 90% of the body burden) remained
in the
hair at the end of that time period. Apparent ingestion of hair
by the
rats during grooming represents a novel form of toxin recirculation.
Transport of both chemical species between blood and tissues
is
bidirectional and symmetric with relatively slow movement into
and out
of the brain. Transport mechanisms for both mercurial species
are
discussed in the context of capillary transport physiology and
the
blood-brain barrier to small molecules and proteins.
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
Excretion of methyl mercury in rat bile: the effect of thioctic
acid,
thionalide, hexadecyl- and octadecylmercaptoacetate.
Author
Refsvik T
Source
Acta Pharmacol Toxicol (Copenh), 50(3):196-205 1982 Mar
Abstract
Thioctic acid markedly increases the sulfhydryl and sulphide
content of
bile. This probably reflects the reduction of thioctic acid in
the
liver, followed by biliary excretion of a reduced derivative.
The total
biliary excretion of methyl mercury was not increased. Thionalide
markedly inhibits biliary excretion of methyl mercury. Simultaneously,
the sulfhydryl and sulphide content of bile decreases. This is
probably
caused by the conjugation of thionalide to glutathione in the
liver,
thereby blocking the biliary excretion of methyl mercury.
Hexadecylmercaptoacetate increases the biliary content of methyl
mercury moderately after a temporary decrease, whereas biliary
sulfhydryl and sulphide concentrations were unchanged.
Octadecylmercaptoacetate does not change the biliary content
of methyl
mercury, sulfhydryl and sulphides significantly. Smaller parts
of
hexadecylmercaptoacetate, octadecylmercaptoacetate and thionalide
seemed to be excreted as such in bile. These results indicate
that
methyl mercury cannot be transported from liver to bile as complexed
to
the sulphides thioctic acid, thionalide, hexa- and
octadecylmercaptoacetate.
Title
Cellular and regional distribution of reduced glutathione in
the
nervous system of the rat: histochemical localization by mercury
orange
and o-phthaldialdehyde-induced histofluorescence.
Author
Philbert MA; Beiswanger CM; Waters DK; Reuhl KR; Lowndes HE
Address
Department of Pharmacology and Toxicology, Rutgers University,
College
of Pharmacy, Piscataway, New Jersey.
Source
Toxicol Appl Pharmacol, 107(2):215-27 1991 Feb
Abstract
Differences in the cellular distribution of antioxidant defense
mechanisms in heterogeneous tissue such as the nervous system
are
likely critical determinants of differential sensitivity to toxicants.
Regional and cellular localization of reduced glutathione (GSH)
in
central and peripheral nervous tissue was determined from the
pattern
of fluorescence observed in tissue sections stained with mercury
orange; localization was confirmed using a novel histofluorochromatic
staining method, o-phthaldialdehyde (OPT). Excellent concordance
between the distribution of fluorescence obtained with mercury
orange
and OPT staining was observed. Depletion of GSH by treatment
with
diethyl maleate resulted in a diminution in both mercury orange
and OPT
histofluorescence. Generally, strong staining of the CNS neuropil
was
seen with little or no observable fluorescence in neuronal somata.
The
cerebellar granular cells were an exception, exhibiting fluorescence
with both mercury orange and OPT. Cerebellar Purkinje cells exhibited
nonuniform fluorescence with mercury orange but generally uniform
staining with OPT. In contrast to the patterns observed in the
CNS, the
sciatic nerve and the sensory cell bodies of the lumbar dorsal
root
ganglia exhibited prominent fluorescence with both mercury orange
and
OPT. Reduced glutathione in the central nervous system appears
primarily localized in the neuropil and white matter tracts;
with a few
exceptions, the neuronal somata do not appear to contain appreciable
amounts of GSH. The heterogeneous distribution of GSH and enzymes
involved in the detoxification and/or excretion of xenobiotics
in the
nervous system may form a basis for selective cellular and/or
regional
expression of neurotoxicity.
Title
Routes for renal transport of methylmercury in mice.
Author
Tanaka T; Naganuma A; Imura N
Address
Department of Public Health, School of Pharmaceutical Sciences,
Kitasato University, Tokyo, Japan.
Source
Eur J Pharmacol, 228(1):9-14 1992 May 1
Abstract
To clarify the routes for renal methylmercury uptake, the effects
of
ureter ligation and pretreatment of probenecid, an organic anion
transport inhibitor, or acivicin, a gamma-glutamyltranspeptidase
(gamma-GTP) inhibitor, on renal methylmercury content were investigated
in mice. For 120 min after CH3HgCl (5 mumol/kg, i.v.) injection,
renal
methylmercury content in bilateral ureter-ligated mice was
approximately 50% lower than that of sham-operate mice. The glomerular
filtration rate was reduced to about 15% of the control by ureter
ligation. These results suggest an important role of glomerular
filtration in the renal methylmercury uptake. Pretreatment with
probenecid (0.5 or 1.0 mmol/kg, i.p.) reduced the renal methylmercury
accumulation 30 min after CH3HgCl injection in a dose-dependent
manner
in both ureter-ligated and sham-operated mice. Urinary methylmercury
excretion was not affected by probenecid pretreatment. Renal
methylmercury content of ureter-ligated mice was not changed
by
pretreatment with acivicin (0.5 or 1.0 mmol/kg. i.p.), which
was
previously reported to decrease the renal methylmercury content
in
mice. Coadministration of GSH (10 mumol/kg, i.v.) with CH3HgCl
increased the renal methylmercury uptake determined 5 min after
injection in ureter-ligated mice. These results suggest that
at least
two transport systems play major roles in renal methylmercury
uptake:
one is a route from the glomeruli through the brush border membrane
which is dependent on the action of gamma-GTP, and the other
route is
the one using an organic anion transport system through the basolateral
membrane.
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
Effect of some chelating agents on the biliary excretion of mercury.
1.
Excretion kinetics and distribution of mercury in the organism.
Author
Cikrt M; Tich¦ M
Source
J Hyg Epidemiol Microbiol Immunol, 24(3):346-55 1980
Abstract
Wistar strain female rats were used to study the impact of
1-cysteine,D,L-penicillamine, EDTA, sodium N,N-diethyldithiocarbamate,
BAL, Unitiou, Spironolactone, Thiomestron and thiophenolacetate
on
excretion kinetics and distribution pattern of 203Hg injected
intravenously in a dose of 120 microgram 203Hg2+ per rat. A
considerably enhanced biliary excretion of mercury was observed
after
pretreatment with Spironolactone, Unitiol, BAL and Thiomestron.
The
action of these agents persisted for only 2--3 hours after mercury
application. The highest urinary excretion of mercury was recorded
after pretreatment with Unitol and BAL. All the tested agents,
particularly thiophenolacetate, turned out to enhance mercury
excretion
through intestinal wall cells. Pretreatment with the tested agents
caused also considerable changes in the pattern of mercury distribution
in the rat organism.
Title
Effect of some chelating agents on the biliary excretion of mercury.
2.
Relationship between the excretion of mercury and its binding
to bile
fractions.
Author
Tich¦ M; Horejsí M; Cikrt M
Source
J Hyg Epidemiol Microbiol Immunol, 24(3):309-23 1980
Abstract
mercury binding to bile components and the correlation between
the
amount of mercury bound in the bile fraction 2 and the rate of
mercury
biliary excretion were studied in female rats exposed to intravenously
injected HgCl2 after pretreatment with a series of 14 chemical
agents.
After pretreatment with the tested agent, 203Hg was detectable
both in
the bile fraction 1 and 2. Distribution pattern of 203Hg between
the
two fractions appeared to be linked with the chemical structure
of the
formed mercury complex. Pretreatment with these agents did not
inhibit
the formation of the bile fraction 3. By their influence on the
203Hg
distribution between the bile fractions 1 and 2, the tested agents
can
be roughly divided into 3 groups: the content of 203Hg in the
bile
fraction 2 is about 10--20% and does not change significantly
within
the first 24 hours after 203 HgCl2 injection (cysteine, penicillamine,
disodium ethylenediaminotetraacetate -- Na2EDTA, sodium
diethyldithiocarbamate, sodium alanindithiocarbamate, acrylonitrile);
the the 203Hg content in the bile fraction 2 increases
(thiophenolacetate); the content of 203Hg in fraction 2 is initially
several times higher than that in the bile fraction 1, but then
decreases during the first 24 hours (2,3-dimercaptopropanol --
BAL,
sodium 2,3-dimercaptopropanesulphonate, spironolactone, Thiomestron).
The rate of mercury biliary excretion (Rb) was found to be closely
correlated with the relative amount of mercury present in the
bile
fraction 2 (a2), if a2 > 30%, both in vivo (Rb = 1.077 a2
+ 0.758) and
invitro (Rb = 1.067 a2 + 0.519) experiments. Practically identical
values of the constant accompanying a2 in the two equations seem
to
indicate that one of the decisive factors influencing the rate
of
mercury biliary excretion in rats is rather the mercury affinity
for
the bile fraction 2 components than the agent-induced mercury
transport
mechanisms. For a2 < 30% the correlation is non-linear and
the
excretion is rather inhibited than enhanced.
Title
Human studies with the chelating agents, DMPS and DMSA.
Author
Aposhian HV; Maiorino RM; Rivera M; Bruce DC; Dart RC; Hurlbut
KM;
Levine DJ; Zheng W; Fernando Q; Carter D; et al
Address
University Department of Molecular and Cellular Biology, University
of
Arizona, Tucson 85721.
Source
J Toxicol Clin Toxicol, 30(4):505-28 1992
Abstract
Meso-2,3-dimercaptosuccinic acid (DMSA) is bound to plasma albumin
in
humans and appears to be excreted in the urine as the DMSA-cysteine
mixed disulfide. The pharmacokinetics of DMSA have been determined
after its administration to humans po. For the blood, the tmax
and t1/2
were 3.0 h + 0.45 SE and 3.2 h + 0.56 SE, respectively. The Cmax
was
26.2 microM + 4.7 SE. To determine whether dental amalgams influence
the human body burden of mercury, we gave volunteers the sodium
salt of
2,3-dimercaptopropane-1-sulfonic acid (DMPS). The diameters of
dental
amalgams of the subjects were determined to obtain the amalgam
score.
Administration of 300 mg DMPS by mouth increased the mean urinary
mercury excretion of subjects over a 9 h period. There was a
positive
correlation between the amount of mercury excreted and the amalgam
score. DMPS might be useful for increasing the urinary excretion
of
mercury and thus increasing the significance and reliability
of this
measure of mercury exposure. DMSA analogs have been designed
and
synthesized in attempts to increase the uptake by cell membranes
of the
DMSA prototype chelating agents. The i.v. administration of the
monomethyl ester of DMSA, the dimethyl ester of DMSA or the zinc
chelate of dimethyl DMSA increases the biliary excretion of platinum
and cadmium in rats.
Title
Comparative investigations on the effects of acute intraperitoneal
cadmium, chromium, and mercury exposure on the kidney.
Author
Bomhard E; Maruhn D; Vogel O
Source
Uremia Invest, 9(2):131-6 1985-86
Abstract
Urinary excretion of lactate dehydrogenase (LDH),
glutathione-S-transferase (GST), leucine arylamidase (LAS),
gamma-glutamyltransferase (GGT), beta-galactosidase (GAL),
beta-N-acetyl-D-glucosaminidase (NAG), sodium, and glucose were
determined in female Sprague-Dawley rats the subsequent three
days
after intraperitoneal treatment with single doses of 4.5 mg CdCl2
X
1H2O/kg, 20 mg Na2CrO4/kg, and 0.75 mg HgCl2/kg body weight.
Although
the pathological effects were localized within the same part
of the
nephron (i.e., the proximal tubule), there were marked differences
with
regard to the extent and time course of the parameters affected.
Treatment with cadmium resulted essentially in a marked decline
in
sodium and glucose excretion. The administration of chromate
led to a
slightly to moderately elevated excretion of the enzyme activities
measured with the cytosolic LDH as the most increased enzyme
(ca. 500%
of controls on Day 3 postadministration). Median glucose excretion
was
unaffected whereas sodium excretion was transiently reduced.
The
maximum of enzyme excretion after HgCl2 was essentially the same
on the
first day postadministration and the amount of enzyme activity
in urine
up to 20 times higher compared to that after chromium. Sodium
excretion
was below that of controls on Days 2 and 3, whereas glucose excretion
was markedly elevated (up to 8000% of controls). The results
indicate
that it is possible to discriminate with the use of selected
urinary
enzymes, substrates, and electrolytes various kinds of nephrotoxic
actions not only in different but also within the same part of
the
nephron.
Title
Mercuric chloride-induced kidney damage in mice: time course
and effect
of dose.
Author
Nielsen JB; Andersen HR; Andersen O; Starklint H
Address
Department of Environmental Medicine, Odense University, Denmark.
Source
J Toxicol Environ Health, 34(4):469-83 1991 Dec
Abstract
The rate of elimination of mercury after a single oral or
intraperitoneal administration of HgCl2 to male or female mice
has
recently been demonstrated to be inversely related to the dose
size
(Nielsen and Andersen, 1989, 1990). The present study demonstrates
dose-related induction of renal tubular damage, followed by
regeneration, after oral administration of HgCl2 to female mice.
Dose-related increased fractional urinary mercury excretion (expressed
as percent of dose) was also demonstrated. At increasing dose
of HgCl2,
the renal activity of selenium-dependent glutathione peroxidase
decreased, and was only 50% of the activity in untreated controls
after
administration of 200 mumol HgCl2/kg. At higher doses, the renal
concentration of glutathione was significantly reduced as well.
The
degree of tissue damage was inversely related to the fractional
deposition of mercury in the kidneys. This study indicates that
the
reduction in fractional whole-body retention of mercury with
increasing
dose size previously demonstrated is due to increased urinary
mercury
excretion during transient renal damage followed by regeneration,
as
extensive leakage took place before extensive regeneration was
noted.
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
Hepatobiliary transport of the anionic organomercury compound
(mersalyl) is carrier mediated.
Author
Thalhammer T; Graf J
Address
Department of General and Experimental Pathology, University
of Vienna,
Austria.
Source
Biochem Pharmacol, 38(19):3223-31 1989 Oct 1
Abstract
The hepatobiliary excretion of the anionic organic mercury compound
(mersalyl) was studied in the isolated perfused rat liver and
in
isolated rat liver plasma membrane vesicles. In the isolated
perfused
liver, mersalyl is immediately taken up from the perfusion medium
and
concentratively excreted into bile. Uptake is characterized by
saturation kinetics (S)0.5 = 20 microM, Vmax = 117 nmoles/min/g
liver,
cooperatively of mersalyl binding sites, stimulation by extracellular
sodium and temperature dependence. Uptake of mersalyl into basolateral
membrane vesicles also exhibits characteristics of a carrier
mediated
transport: saturation kinetics (S)0.5 = 28 microM, Vmax = 1.6
nmoles/min/mg protein, dependence on extravesicular sodium,
cooperativity of mersalyl binding sites, temperature dependence
and
transstimulation by intravesicular non-radioactive mersalyl.
Uptake was
inhibited by alpha-naphthylacetic acid and mercapto group reagents,
indicating involvement of mercapto groups on the carrier and
a binding
site for carboxylic anions. Data from the isolated perfused liver
and
from isolated basolateral vesicles indicate that mersalyl uptake
into
the liver is carrier mediated. Uptake mechanism and driving forces
appear analogous to those for the uptake of chemically related
compounds such as taurocholic acid. Therefore it is speculated
that
mersalyl may be transported by carrier molecules which apparently
accept numerous chemically unrelated compounds. |
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