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)

Carbon tetrachloride and bromotrichloromethane are both metabolized by cytochrome P-450 in the presence of phenyl-N-t-butyl nitrone PBN) to the PBN/trichloromethyl (PBN/.CCl3) and the PBN carbon dioxide anion (PBN/.CO2-) radical adducts in the liver. The formation of the latter but not the former species in perfused liver was reduced markedly by prior depletion of hepatic glutathione with either diethyl maleate or buthionine sulfoximine treatments. In microsomal incubations, the PBN/.CO2- radical adduct was detected only upon the addition of cytosol. In microsomal incubations containing PBN, CCl4, and GSH, but no added cytosol, a novel radical adduct with distinctive coupling constants was detected. This radical adduct's ESR spectrum exhibited 13C isotope effects when it was formed in an incubation containing 13CCl4 or Br13CCl3. The presence of GSH in the radical adduct is postulated based on the radical adduct's hydrophilicity and slow rate of rotation in solution. The detection of this new radical adduct, PBN/[GSH-.CCl3], establishes the reaction of GSH with a CCl4-derived free radical as a significant event in the metabolism of CBrCl3 and CCl4. The cytosolic conversion of PBN/[GSH-.CCl3] into PBN/.CO2- has been demonstrated and characterizes the PBN/.CO2- radical adduct as the product of metabolism of PBN/[GSH-.CCl3], a primary radical adduct. Thus, it is concluded that GSH rather than oxygen is obligatory for the formation of PBN/.CO2- from .CCl3 in intact cells.
 ...
PMID:Reaction of glutathione with a free radical metabolite of carbon tetrachloride. 215 56

Cocaine has been associated with hepatotoxicities in man and is a potent hepatotoxin in mice. The theorized toxic metabolite of cocaine is thought to be generated by a multistep pathway mediated primarily by cytochrome P-450. Ethanol, whether administered acutely or chronically, is known to have diverse effects on numerous hepatocellular biochemical pathways. The present study was designed to characterize not only the effects of acute and chronic ethanol on cocaine-mediated hepatotoxicity but also on the hepatic reduced glutathione (GSH) in an attempt to correlate depletions of GSH with changes in toxicity. Male and female mice were administered an acute 50 mg/kg dose of cocaine either 1 hr after an acute 3 g/kg dose of ethanol, or after 5 days of consuming an ethanol-containing liquid diet. Serum alanine aminotransferase (ALT) activity was measured in blood collected 24 hr after the acute cocaine dose. In addition, hepatic reduced glutathione (GSH) and cytochrome P-450 content were measured at the point in the pretreatment where cocaine was administered. The results of this study indicate that both acute and chronic ethanol pretreatment can markedly enhance the hepatotoxicity of cocaine in both male and female mice and that the enhancement is significantly greater after chronic ethanol pretreatment. Hepatic GSH was slightly decreased 1 hr after an acute dose of ethanol and significantly decreased after chronic ethanol consumption.(ABSTRACT TRUNCATED AT 250 WORDS)
 ...
PMID:Potentiation of cocaine-mediated hepatotoxicity by acute and chronic ethanol. 217 68

The hepatic glutathione (GSH) system and the influences of xenobiotics have been reviewed. Key steps in the regulation of hepatic GSH are GSH biosynthesis, the GSH-peroxidase/reductase cycle, the cystathionine pathway, and the carrier-mediated export processes. Influences of xenobiotics on these different pathways are discussed. Xenobiotics may lead to liver injury after biotransformation to highly reactive electrophilic metabolites (mainly cytochrome P-450 mediated), which easily conjugate with GSH, thus producing GSH depletion. This GSH depletion and probably an additional loss of protein sulfhydryl groups cause a disturbance of the intracellular calcium homeostasis which leads to an irreversible cell injury. The different acinar distribution of cytochromes P-450 and of GSH and GSH-related detoxication pathways points to a greater susceptibility of perivenous hepatocytes to xenobiotic-induced damage. Also, the intracellular compartmentation of GSH is important for the understanding of hepatocellular injury induced by several xenobiotics.
 ...
PMID:The hepatic glutathione system--influences of xenobiotics. 219 11

1. The involvement of glutathione (GSH) and cytochrome P-450 in the conversion of theobromine to 6-amino-5-(N-methylformylamino)-1-methyluracil (3,7-DAU) and 3,7-dimethyluric acid (3,7-DMU) has been investigated in rat liver microsomal incubations. 2. The ratio of formation of 3,7-DAU to 3,7-DMU increased with increasing GSH concentration, reaching a maximum (approximately 12:1) at 2 mM. For any given added GSH concentration the formation of 3,7-DAU plus 3,7-DMU remained constant. 3. 3,7-DAU and 3,7-DMU formation were increased approx. 12- and 1.6-fold in liver microsomes from rats treated with 3-methylcholanthrene and phenobarbitone, respectively. Cimetidine, metyrapone and SKF-525A each inhibited the conversion of theobromine to 3,7-DAU and 3,7-DMU. 4. Apparent Km and Vmax values for the combined formation of 3,7-DAU and 3,7-DMU were the same in the absence and presence of GSH, 2 mM. 5. L-Cysteine and N-acetyl-L-cysteine were as effective as GSH in causing a shift from 3,7-DMU to 3,7-DAU formation, but the non-thiol reducing agents ascorbic acid and alpha-tocopherol were ineffective. 6. Data are consistent with the hypothesis that 3,7-DAU and 3,7-DMU are derived from a common oxidized intermediate of theobromine, the formation of which is rate-limiting. The putative intermediate normally serves as a precursor to 3,7-DMU but in the presence of GSH, or some other cellular thiol, it may be reduced to give 3,7-DAU.
 ...
PMID:Mechanism of formation of 6-amino-5-(N-methylformylamino)-1-methyluracil and 3,7-dimethyluric acid from theobromine in the rat in vitro: involvement of cytochrome P-450 and a cellular thiol. 221 65

The influence of Monensin, Tiamulin and the simultaneous administration of the two substances on the microsomal, mixed function oxidases was studied on cockerels. Monensin was seen to cause a slight depression in the amount of cytochrome P-450 and cytochrome b5 as well as in the activities of aniline-p-hydroxylase, p-nitrophenol-hydroxylase and p-nitroanisole-O-demethylase. Tiamulin induced a moderate increase in the amount of cytochrome P-450 and in the activities of aniline-p-hydroxylase, p-nitrophenol-hydroxylase and aminopyrine-N-demethylase. The combined administration of monensin and tiamulin resulted in marked induction of the microsomal enzymes; the amount of cytochrome P-450 reduced by metyrapone or carbon monoxide increased 2.5 or 2-times, respectively, and the activities of the tested microsomal hydroxylases and demethylases showed also an expressed increase. At the same time the formation of lipid peroxides also markedly increased and the GSH concentration was reduced. In conclusion, the results of the investigations indicate that the simultaneous application of monensin and tiamulin cause a marked induction of the drug-metabolizing microsomal enzymes and a significant increase in the lipid peroxide formation.
 ...
PMID:[The effect of monensin, tiamulin and the simultaneous administration of both substances on the microsomal mixed function oxidases and on the peroxide formation in broilers]. 224 30

Treatment of rats with cisplatin or with cisplatin after chronic pre-exposure to lead induced a decrease in cytochrome P-450, reduced glutathione (GSH), GSH-S-transferase, reductase and peroxidase activities, and an increase in N-glucuronyl transferase, lipid peroxidation and oxidized glutathione (GSSG). On histological examination, rats treated by lead or cisplatin and by lead + cisplatin revealed significant proximal tubular lesions which varied from minimal changes to severe necrosis. Lead toxicity was characterized by irregularity and thickening of glomerular basement membranes, and by tubular mitochondrial alterations associated with the presence of intranuclear inclusions. Cisplatin injury showed more extensive lesions with cellular disorganization. Except for an increase in N-glucuronyl transferase activity, lead did not exert any significant effect on these biochemical and histological parameters and did not significantly modify the deleterious effects of further therapy by cisplatin.
 ...
PMID:Cisplatin nephrotoxicity in lead-pretreated rats: enzymatic and morphological studies. 230 43

The role of thiols (nonprotein and protein) in the metabolic activation of phenytoin was examined. In vitro phenytoin covalent binding and metabolite formation were determined in hepatic microsomes from A/J mice. Covalent binding of a phenytoin-reactive intermediate to microsomal protein was linear with respect to time, protein concentration and phenytoin concentration. Covalent binding was inhibited by inhibitors of cytochrome P-450. Inducers of cytochrome P-450 enhanced phenytoin covalent binding as follows: phenobarbital greater than 3-methylcholanthrene greater than saline-treated controls. Low molecular weight thiols (GSH, cysteine and cysteamine), a thiol generator (methylthiazolidine carboxylate), and thiol modifying agents (N-ethylmaleimide, mercuric chloride and diamide) significantly inhibited covalent binding. Amino acids other than cysteine did not decrease the covalent binding. Formation of the metabolites, para-hydroxyphenytoin and phenytoin dihydrodiol, was greater following preincubation with GSH or cysteine. In summary, protein thiol groups appear to be important sites for in vitro covalent binding of a reactive intermediate of phenytoin. These data suggest glutathione may protect membrane-bound enzymes responsible for phenytoin metabolism from attack by an electrophilic or free radical reactive intermediate of phenytoin and GSH may inactivate a phenytoin-reactive metabolite by formation of a putative glutathione conjugate.
 ...
PMID:Covalent binding of phenytoin to protein and modulation of phenytoin metabolism by thiols in A/J mouse liver microsomes. 231 74

The nematocide and soil fumigant 1,2-dibromo-3-chloropropane (DBCP) is a carcinogen and a mutagen and displays target-organ toxicity to the testes and the kidney. It has been proposed that both cytochrome P-450 mediated activation and glutathione (GSH) conjugation pathways are operative in DNA damage and organotropy induced by DBCP. To determine the chemical mechanisms involved in the bioactivation of DBCP and to assess a role for an episulfonium ion intermediate, the mechanism of formation of GSH conjugate metabolites of DBCP was investigated. Five biliary GSH conjugates of DBCP were isolated from rats and identified by fast atom bombardment tandem mass spectrometry: S-(2,3-dihydroxy-propyl)glutathione (I), S-(2-hydroxypropyl)glutathione (IIA), S-(3-chloro-2-hydroxypropyl)glutathione (III), 1,3-di(S-glutathionyl)propan-2-ol (IV), and 1-(glycyl-S-cysteinyl)-3- (S-glutathionyl)propan-2-ol (V). The mechanisms of conjugate formation were addressed by assessing deuterium retention in conjugates derived from [1,1,2,3,3-2H5] DBCP (D5-DBCP). GSH conjugates I, III, IV, and V displayed quantitative retention of deuterium, an observation consistent with the formation of an episulfonium ion intermediate. GSH conjugate IIA, however, retained three atoms of deuterium, thus invoking a P-450 mechanism in its genesis. The involvement of glutathione transferase (GST) and sequential episulfonium ion intermediates in the formation of metabolites I, III, and IV was demonstrated in vitro. Upon incubation of DBCP with GST, metabolites I, III, and IV were identified by tandem mass spectrometry and were found to arise with quantitative retention of deuterium when D5-DBCP was employed as a substrate. An additional GSH conjugate, 1,2,3-tri(S-glutathionyl)propane (VI), was observed as the major metabolite in incubations of GST with DBCP. When the incubations of DBCP with GST were performed in H2(18)O, metabolite I incorporated two atoms of 18O, and metabolites III and IV incorporated one atom of 18O. The ability of GST to catalyze the formation of the four GSH conjugates observed in vivo, with quantitative retention of deuterium and incorporation of 18O from H2(18)O, may be rationalized by a mechanism invoking the initial formation of S-(2-bromo-3-chloropropyl)glutathione. Rearrangement of this unstable conjugate via several reactive episulfonium ions, with either hydrolysis by water or alkylation of GSH at various stages, would account for the pattern of metabolites and their status of isotopic enrichment observed under various incubation conditions.(ABSTRACT TRUNCATED AT 400 WORDS)
 ...
PMID:Metabolic activation of 1,2-dibromo-3-chloropropane: evidence for the formation of reactive episulfonium ion intermediates. 236 69

Metronidazole (MNZ), an antiprotozoan and antibacterial agent, has been shown to yield DNA-damaging reactive species after nitroreductive biotransformation. The genotoxic effect of MNZ was studied in primary cultures of both rat and human hepatocytes. In millimolar concentrations MNZ produced DNA fragmentation, as measured by the alkaline elution technique, and unscheduled DNA synthesis, as evaluated by quantitative autoradiography, in rat hepatocytes. The amount of DNA damage was directly related to the dose and the length of exposure, was increased by hypoxia and GSH depletion, and was markedly reduced by inhibition of cytochrome P-450 activity. In the same experimental conditions human hepatocytes resulted constantly more resistant than rat hepatocytes to the genotoxic activity of MNZ. These findings suggest that the rat hepatocyte model might be an inappropriate predictor of nitroimidazoles genotoxicity.
 ...
PMID:Comparison of the sensitivity of human and rat hepatocytes to the genotoxic effects of metronidazole. 237 Dec 38

Chlordecone (CD) pretreatment is known to markedly potentiate CCl4 hepatotoxicity. Previous studies have shown that prior exposure to CD obtunds the increased hepatocellular regeneration and repair observed in non-treated rats challenged with a single, low dose of CCl4. These observations allowed us to hypothesize that suppression of hepatic regeneration and tissue repair by CD + CCl4 combination treatment might be involved in this interaction. To test this hypothesis, CCl4 hepatotoxicity was evaluated in actively regenerating livers using CD-treated (10 ppm in the diet for 15 days), surgically partially hepatectomized (PH) male Sprague-Dawley rats. Rats undergoing no surgical manipulation (CTRL) and sham operation (SH) were included as appropriate controls. Surgical manipulations were conducted on day 15 of the dietary protocol. Based on liver-to-body weight ratios (LW/BW), mitotic indices, hepatic cytochrome P-450 content, and hepatic glutathione (GSH and GSSG) levels, PH-induced hepatocellular regeneration was not affected by pretreatment with CD. Thus, the PH model was considered valid for assessing the effects of CD + CCl4 combination treatment. CCl4 (100 microliter/kg; i.p.) was administered 1, 2, 4 or 7 days after the surgical manipulations. Hepatotoxicity was assessed 24 h later by measuring LW/BW and serum enzymes (SGPT, SGOT and ICD) in all four groups. Hepatic histopathological, histomorphometric and lethal effects were assessed in animals receiving CCl4 1 or 7 days after the surgical manipulations. CCl4-induced increases in LW/BW were observed in CD + PH rats receiving CCl4 4 or 7 days post-PH, but not in the 1 or 2 day post-PH groups in which the hepatocellular regeneration was maximal. CCl4-induced serum enzyme elevations were significantly less in the CD + PH rats as compared to CD + SH. This decrease in the serum enzyme elevations was most prominent in the 1 day post-PH group, where the hepatocellular mitotic activity was most pronounced. CCl4 lethality, assessed in the 1 day post-surgical manipulation group, was also decreased in the CD + PH rats in comparison to CD + SH rats. Such a protection was not observed in rats receiving CCl4 7 days post-PH. These data are consistent with and are supportive of the hypothesis that a suppression of otherwise normally stimulated hepatocellular regeneration following low-dose CCl4 administration is involved in the marked amplification of CCl4 toxicity by CD.
 ...
PMID:Protection of chlordecone-potentiated carbon tetrachloride hepatotoxicity and lethality by partial hepatectomy. 245 51


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