Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:6.3.2.3 (glutathione synthetase)
 678 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

N-Acetylcysteine (NAC) is protective against acetaminophen-induced hepatotoxicity primarily by providing precursor for the glutathione synthetase pathway, while cysteamine has been demonstrated to alter the cytochrome P-450 dependent formation of toxic acetaminophen metabolite. Mice administered acetaminophen (500 mg/kg) had elevations of serum alanine aminotransferase (ALT) to 273.0 +/- 37.5 and 555.8 +/- 193.4 U/mL at 12 and 24 h, respectively, after injection. Administration of cysteamine (100 mg/kg) or NAC (500 mg/kg) significantly reduced serum ALT activity (p less than 0.001). Reducing the dose of NAC or cysteamine by 50% greatly reduced their hepatoprotective effect while the co-administration of the reduced doses of NAC (250 mg/kg) and cysteamine (50 mg/kg) following acetaminophen overdose prevented elevation of serum ALT activity (39.2 +/- 1.17 and 32.5 +/- 5.63 U/mL at 12 and 24 h post-injection, p less than 0.001) and preserved normal mouse hepatic histology. Neither NAC (500 mg/kg), cysteamine (100 mg/kg), or the lower doses in combination of both agents were found to alter the half-life or peak levels of acetaminophen. Liver microsomal aryl hydrocarbon hydroxylase activity measured 24 h after drug administration was not significantly different between treatment groups and controls receiving only saline. These results indicate a possible role for the concomitant use of NAC and cysteamine in the prevention of hepatic necrosis following toxic doses of acetaminophen. Neither decrease in plasma acetaminophen levels nor depression of cytochrome P-450 enzyme activity appears to be the mechanism of protection when these doses of NAC, cysteamine, or both drugs together are administered with a toxic dose of acetaminophen in mice.
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PMID:Cysteamine in combination with N-acetylcysteine prevents acetaminophen-induced hepatotoxicity. 158 51

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.
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PMID:Paradoxical effect of cobaltous chloride on carbon disulfide induced hepatotoxicity in rats. 317 44

Evaluation of idiosyncratic drug reactions in predisposed individuals is limited by ethical concerns arising from rechallenge with the suspected offending agent. A previously developed in vitro method using human lymphocytes and a murine microsomal drug metabolizing system has been used to examine toxicity due to acetaminophen (APAP), sulfonamide antibiotics and aromatic anticonvulsants. An improved method is described in which toxic APAP metabolites are generated by a purified and reconstituted cytochrome P-450 system, minimizing the amount of exogenous detoxification enzymes in the assay. Toxicity is assessed by an objective, automated method based on the reduction of 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide to an insoluble purple formazan by the mitochondria of viable cells and correlates with that based on trypan blue exclusion. Toxicity required cytochrome P-450 and NADPH, and was inhibited by SKF 525A. Exogenous glutathione also decreased toxicity in a concentration-dependent manner. Lymphocytes from a glutathione synthetase-deficient patient exhibited markedly enhanced toxicity to APAP exceeding the 95% CL of 10 control subjects over a concentration range of 10 to 1000 micrograms/ml. The data are consistent with the generation of cytochrome P-450-dependent reactive metabolites which subsequently can be detoxified by glutathione. This method allows one to address specifically individual differences in detoxification pathways. The use of an automated assessment of cell viability may prove useful in preclinical screening of new compounds for their propensity to cause "idiosyncratic" drug reactions in a predisposed population.
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PMID:Drug metabolite toxicity assessed in human lymphocytes with a purified, reconstituted cytochrome P-450 system. 338 48