Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C1260386 (GSH)
 38,102 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

A single acute dose of carbon disulfide (CS2, 5 mmol/kg ip) caused hepatic damage in rats pretreated with phenobarbital. Rats pretreated with phenobarbital and cobaltous chloride (CoCl2, 250 mumol/kg sc) were protected against CS2 induced hepatotoxicity. When single acute doses of CS2 and CoCl2 were given at the same time, however, rats developed a much more severe hepatic lesion than that seen following CS2 alone. Similar cotreatment of CoCl2 with bromobenzene, carbon tetrachloride or thioacetamide did not enhance the hepatotoxicity of these well-studied hepatotoxins. Additionally, other divalent metal salts (CuSO4 and ZnCl2) did not enhance CS2 hepatotoxicity. Hence, the interaction between CS2 and CoCl2 (that results in enhanced CS2 induced hepatic damage) appears to be relatively specific for these two agents. CS2 caused an approximate 50% decrease in hepatic cytochrome P-450 when given alone, but an approximate 85% decrease when given with CoCl2. This observation supports the hypothesis that the breakdown products of cytochrome P-450 heme are responsible for CS2 induced hepatotoxicity. In addition, single doses of CS2 or CoCl2 caused increases of 30 to 60% in hepatic glutathione (GSH), but additive responses were not obtained when the two agents were given at the same time. GSH synthetase and gamma-glutamyl transpeptidase activity were inconsistently changed by these treatments, and did not provide a consistent explanation for the increases in GSH. The enhanced hepatotoxicity of CS2 + CoCl2 is not due to changes in hepatic glutathione metabolism.
 ...
PMID:Paradoxical effect of cobaltous chloride on carbon disulfide induced hepatotoxicity in rats. 317 44

1. The metabolism of 14C-hexachloro-1,3-butadiene (HCBD) was studied in mice and in subcellular fractions from mouse liver and kidney. 2. In the presence of glutathione (GSH), liver microsomes and cytosol transformed HCBD to S-(pentachlorobutadienyl)glutathione (PCBG). PCBG formation in subcellular fractions from mouse kidney was very limited. Oxidative metabolism of HCBD by cytochrome P-450 could not be demonstrated. 3. Cysteine conjugate beta-lyase was present in mitochondria and cytosol from mouse liver and kidney. 4. After an oral dose of 30 mg/kg 14C-HCBD, mice eliminated 67.5-76.7% of dose in faeces; urinary elimination accounted for 6.6-7.6%. 5. Metabolites of HCBD identified are: S-(pentachlorobutadienyl)glutathione in faeces; S-(pentachlorobutadienyl)-L-cysteine, N-acetyl-S-(pentachlorobutadienyl)-L-cysteine and 1,1,2,3-tetrachlorobutenoic acid in urine. 6. The results suggest that conjugation of HCBD with GSH in liver, followed by renal processing of the glutathione S-conjugates and beta-lyase-catalysed formation of reactive intermediates, accounts for the organ specific toxicity of HCBD in mice.
 ...
PMID:Metabolism of hexachloro-1,3-butadiene in mice: in vivo and in vitro evidence for activation by glutathione conjugation. 317 19

Severity of liver damage 24 hr after i.p. administration of acetaminophen in doses of 0.4 and 0.8 g/kg was evaluated in male Fischer 344 rats at 4, 14 and 25 months of age. Both doses of acetaminophen produced significant elevations of serum alanine aminotransferase (ALT) and sorbitol dehydrogenase (SDH) activities in 4-month-old rats. Enzyme release was somewhat diminished in old age. Hepatic glutathione (GSH) and microsomal cytochrome P-450 concentrations were decreased in rats that received 0.8 g/kg of acetaminophen. The decreases occurred in young-adult and middle-aged rats, but not in old rats. The results demonstrated that old age does not enhance the hepatotoxic effects of acetaminophen in male Fischer 344 rats.
 ...
PMID:Acetaminophen hepatotoxicity in aging rats. 318 Oct 38

We investigated the role of microsomal lipid peroxidation in halothane hepatotoxicity in guinea pigs. Animals were exposed to halothane, isoflurane or enflurane. Enhancement of microsomal lipid peroxidation was specific to halothane. The time-course of lipid peroxidation and hepatic damage following a single exposure to halothane was investigated by measuring the thiobarbituric acid (TBA)reactive products, serum transaminase activity, reduced glutathione (GSH) concentration and histopathological examination. Microsomal lipid peroxidation was enhanced most rapidly and preceded GSH depletion and hepatic injury. Metyrapone, an inhibitor of cytochrome P-450, and N-tert-butyl-alpha-phenylnitrone (BPN), a radical trapping agent, inhibited halothane-induced lipid peroxidation and the incidence and severity of liver injury. The metabolism of halothane was considered to be inhibited by metyrapone and the reactivity of radical intermediates was considered to be decreased by BPN. Microsomal lipid peroxidation was initiated by radical metabolites of halothane but did not result from GSH depletion. Inhibition of microsomal lipid peroxidation reduced the halothane hepatotoxicity. These results demonstrated that the halothane-induced liver injury was caused by microsomal lipid peroxidation in guinea pigs.
 ...
PMID:Halothane-induced liver injury as a consequence of enhanced microsomal lipid peroxidation in guinea pigs. 318 93

The objective of this study was to examine the effect of chronic inhibition of glutathione (GSH) biosynthesis on cholesterol and bile acid metabolism in rats. Male Sprague-Dawley rats, weighing between 60 and 65 g, were randomly assigned to one of two groups and allowed a 1-week adaptation period to a 6 a.m.-6 p.m. light cycle. Food and water were available ad libitum. Following the adaptation period, 1 group was given a solution of 30 mM DL-buthionine sulfoximine (BSO, an inhibitor of GSH biosynthesis) in saline, while the other group received saline only. All studies were carried out during, or at the end of the second week of BSO treatment. While body weight was minimally affected by BSO treatment, liver weight (% of body weight) was significantly greater in the BSO group (control 4.8 +/- 0.2 vs. BSO 5.2 +/- 0.3; P less than 0.05). The increase in liver weight, however, was not associated with a change in the specific content of cytochrome P-450. Even though fecal output (g/100 g per day) was significantly greater in the BSO group (control 2.4 +/- 0.1 vs. BSO 2.7 +/- 0.3; P less than 0.05), it was not commensurate with an increase in fecal bile acids and neutral sterols. In fact, fecal bile acid excretion (mg/100 g per day) was significantly reduced in the BSO group (control 9.0 +/- 2.0 vs. BSO 6.2 +/- 0.9; P less than 0.05), a finding consistent with a significant reduction in bile acid pool size (mg/100 g) in that group (control 23.1 +/- 1.9 vs. BSO 14.3 +/- 4.8; P less than 0.05). Hepatic GSH content (mumol/g) and cholesterol 7 alpha-hydroxylase activity (pmol/mg per min) were assayed at two time points: 12-2 a.m. (mid-dark point) and 12-2 p.m. (mid-light point). At mid-dark point, BSO-treated animals had a significantly lower hepatic GSH content (control 4.5 +/- 0.3 vs. BSO 0.6 +/- 0.3; P less than 0.05) and a significantly lower cholesterol 7 alpha-hydroxylase activity (control 33.5 +/- 1.3 vs. BSO 14.7 +/- 3.9; P less than 0.05). At mid-light point, hepatic GSH content in the two groups was similar to that at mid-dark point. While cholesterol 7 alpha-hydroxylase activity in both groups was significantly lower (P less than 0.05) at mid-light point relative to that at mid-dark point, there was no difference between the two groups in cholesterol 7 alpha-hydroxylase activity at mid-light point.(ABSTRACT TRUNCATED AT 400 WORDS)
 ...
PMID:Effects of chronic inhibition of glutathione biosynthesis on cholesterol and bile acid metabolism in rats. 319 22

Hepatic GSH conjugation is the initial step in the mammalian biotransformation of hexachloro-1,3-butadiene (HCBD) and analogous haloalkenes. The present paper reports an in vitro investigation of the glutathione-dependent conversion of HCBD to water-soluble products, i.e. the enzyme-catalyzed conjugation of HCBD with GSH. The method employed avoids artifacts due to the volatility, low solubility and hydrophobic nature of the chloro-carbon substrate. In order to assess the relative importance of membrane-bound and cytosolic glutathione S-transferase in the conjugation process, microsomal and cytosolic fractions from adult rat liver were tested separately for their ability to promote water solubilisation of the substrate. In addition, microsomal purified and liposomally reconstituted glutathione S-transferase, were tested. The reaction exhibited Michaelis-Menten kinetics, and conjugation rates were linear for at least 20 min. The hepatic microsomal fraction metabolized HCBD 116 times faster than the cytosolic fraction when substrate saturated. Both mono- and bis-substituted conjugates were formed by microsomal as well as by the cytosolic fraction. Treatment of animals with inducers and the use of specific inhibitors indicated absence of cytochrome P-450 involvement in the formation of water soluble HCBD metabolites and supported the view that microsomal glutathione S-transferase is more important in catalyzing GSH conjugation of this haloalkene than the cytosolic forms of transferases.
 ...
PMID:Features of microsomal and cytosolic glutathione conjugation of hexachlorobutadiene in rat liver. 320 1

1. Primaquine (PQ) often causes severe anaemia in individuals with glucose 6-phosphate dehydrogenase (G6PD) deficient erythrocytes, and metabolites have been implicated as the toxic substance. These studies present data identifying additional metabolites of PQ. 2. Two metabolites of primaquine (PQ) previously identified in human studies, namely, 6-methoxy-8-aminoquinoline (MAQ) and 8-(3-carboxy-1-methylpropylamino)-6-methoxyquinoline (PQC) were also formed on incubation of PQ with hamster liver fractions for up to 24 h without an NADPH-generating system. 3. The alcohol (PQAOH) and lactam (PQLT) derivatives of PQ were also formed on incubation with hamster liver fraction used in these studies. 4. The microsomal metabolism of PQ was decreased in presence of an NADPH-generating system, but not by SKF-525A or glutathione (GSH) indicating that the oxidative reactions were probably not due to the cytochrome P-450 system or free radical mechanisms.
 ...
PMID:Effects of an NADPH-generating system on primaquine degradation by hamster liver fractions. 324 12

Vitamin A deficiency causes a significant decrease in superoxide dismutase, glutathione peroxidase and GSH levels. Simultaneously, it causes a marked increase in Phase I microsomal oxidation (cytochrome P-450, aniline hydroxylase, PNA-O-demethylase) as well as in enzymatic and non-enzymatic lipid peroxidation in lung. Among Phase II enzymes, cytosolic chlorodinitrobenzene glutathione-S-transferase (CDNB-GST) activity showed a significant increase whereas microsomal UDP-glucuronyl transferase and cytosolic p-nitrobenzoyl chloride- and dichloro nitrobenzyl chloride-S-transferase activities showed variable decrease reflecting an imbalance in the Phase I and Phase II enzyme systems. CDNB-GST and non-Se-GSH-Px, registered a parallel rise with pulmonary cytochrome P-450, aniline hydroxylase and O-demethylase, as an adaptive response to elevated Phase I enzyme activity.
 ...
PMID:Effect of vitamin A deficiency on pulmonary defense systems of guinea pig lung. 324 89

The elimination and metabolism of [14-C]-tetrachloroethylene (Tetra) was studied in female rats and mice after the oral administration of 800 mg/kg [14-C]-Tetra. Elimination of unchanged Tetra was the main pathway of elimination in both species and amounted to 91.2% of the dose in rats and 85.1% in mice. [14-C]-Carbon dioxide (CO2) was found to be a trace metabolite of [14-C]-Tetra. Only a small part of the applied dose was transformed to urinary (rats = 2.3%, mice = 7.1%) and fecal (rats = 2.0%, mice = 0.5%) metabolites. The urinary metabolites were separated and quantified by high performance liquid chromatography (HPLC) and identified by gas liquid chromatography/mass spectrometry (GC/MS). The following metabolites could be identified: oxalic acid (8.0% of urinary radioactivity in rats, 2.9% in mice), dichloroacetic acid (5.1%, 4.4%), trichloroacetic acid (54.0%, 57.8%), N-trichloroacetyl-aminoethanol (5.4%, 5.7%), trichloroethanol, free and conjugated (8.7%, 8.0%), S-1,2,2-trichlorovinyl-N-acetylcysteine (N-acetyl TCVC) (1.6%, 0.5%), and another conjugate of trichloroacetic acid (1.8%, 1.3%). The structures of the identified metabolites indicate two different pathways operative in Tetra biotransformation: cytochrome P-450-mediated epoxidation forming reactive metabolites in the liver and conjugation of Tetra with glutathione (GSH) catalyzed by glutathione transferase(s). The formation of reactive intermediates by renal processing of the glutathione conjugates may provide a molecular mechanism for the nephrotoxicity and nephrocarcinogenicity of Tetra in male rats.
 ...
PMID:Identification of S-1,2,2-trichlorovinyl-N-acetylcysteine as a urinary metabolite of tetrachloroethylene: bioactivation through glutathione conjugation as a possible explanation of its nephrocarcinogenicity. 327 76

The role of conjugating enzymes is best understood by looking at the interaction between phase I (mostly cytochromes P-450) and phase II (conjugation) enzymes of drug metabolism. A balance between phase I and II enzymes of detoxication largely determines the disposition to drug toxicity. Reactive electrophilic metabolites, generated by phase I enzymes, are often controlled by GSH-transferases, whereas nucleophilic metabolites such as phenols are controlled by UDP-glucuronosyltransferases (GT) and sulfotransferases. It is more and more recognized that the control of the more stable and more abundant nucleophiles is as important as the control of electrophiles, since the former can be readily converted to electrophiles. For example, phenols and quinols can undergo quinone/quinol redox-cycles with the generation of reactive oxygen species. In the case of benzo(a)pyrene-3,6-quinol toxicity can be prevented by glucuronidation. Conjugating enzymes consist of families of isoenzymes with distinct but overlapping substrate specificity. Rather than dealing with individual isoenzymes, adaptive programs are emphasized by which gene expression of a battery of phase I and II enzymes is turned on by certain types of inducing agents. Mechanistically best known is the program turned on by 3-methylcholanthrene-type inducers which includes enhanced synthesis of certain isoenzymes of cytochrome P-450, GT and probably GSH-transferase. The program may adapt the organism to efficiently detoxify and eliminate aromatic compounds such as benzo(a)pyrene. Evidence is presented that this program exists in both rodents and humans.(ABSTRACT TRUNCATED AT 250 WORDS)
 ...
PMID:The role of conjugation reactions in detoxication. 330 11


<< Previous 1 2 3 4 5 6 7 8 9 10 Next >>