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

Toxic effects of SO2 and sulfite such as bronchitis and bronchoconstriction have been well documented. SO2 has also been suggested to potentiate carcinogenic effects of PAH. However, the molecular basis of these toxic effects is unclear. We have examined the covalent reaction of SO2 and sulfite with cellular proteinacious and nonproteinaceous sulfhydryl compounds using rat liver, and lung and human lung derived A549 cells. Reactions of sulfite and protein in rat and human lung cells reveals at least three proteins with sulfite-reactive disulfide bonds. Besides fibronectin and serum albumin, which had been reported to contain sulfonated products following exposure to sulfite, we have found one other protein with sulfite-binding capabilities. Since the integrity of disulfide bonds is crucial to the tertiary structure and thus protein function, the disruption of protein structure by sulfitolysis may result in altered cellular activities leading to biochemical lesions. Using carefully controlled conditions, reproducible GSH contents can be found in cultured cells and used as an experimental basis for studying alterations in the GSH and GSSG content of cells. Sulfitolysis of GSSG results in the formation of GSSO3H in A549 cells, and possibly in the lung. GSSO3H can be reduced enzymatically by GSSG reductase. However, the Km of GSSO3H is high compared to that of GSSG, suggesting the existence of a transient concentration of GSSO3H once it is formed. Cysteine S-sulfonate is, however, not reduced by cytosolic extracts in the presence of NADPH and would have to be eliminated from the cell by other means. GSSO3H is a strong competitive inhibitor of GST in rat liver and lung and A549 cells, using 1-chloro-2,4-dinitrobenzene as a substrate. It also inhibits the formation of GSH conjugates of BP 4,5-oxide, anti and syn BPDE, but to a lesser extent. These results suggest that SO2 may affect the detoxification of xenobiotic compounds by inhibiting, via formation of GSSO3H, the enzymatic conjugation of GSH and reactive electrophiles. Since GSH conjugation represents the major pathway of elimination of BP epoxides in the lung, our results offer a possible explanation for the cocarcinogenicity of SO2 with PAHs. These data suggest that the sulfitolysis reaction of sulfite is the common reaction mechanism mediating the underlying biochemical reactions leading to both the toxic and cocarcinogenic properties of SO2. Quantitation of sulfitolysis products and their interaction with cellular processes should provide a coherent scheme relating SO2 and sulfite toxicity among animal species and humans.
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PMID:Covalent reactions in the toxicity of SO2 and sulfite. 376 76

The thymine hydroperoxide, 5-hydroperoxymethyluracil, is a substrate for Se-dependent glutathione (GSH) peroxidase and the Se-independent GSH peroxidase activity associated with the GSH transferase fraction. These enzymes may contribute to repair mechanisms for damage caused by oxygen radicals. GSH transferases 1-1, 2-2, 3-3, 4-4, 6-6, and 7-7 [(1984) Biochem. Pharmacol. 33, 2539-2540] are shown to differ considerably in their ability to utilize this substrate. For example, high activity is found in GSH transferase 6-6 which is the major isoenzyme in spermatogenic tubules where DNA synthesis is so active and faithful DNA replication so important. The activity of the purified GSH transferase isoenzymes towards 5-hydroperoxymethyluracil is comparable with their activity towards other endogenous substrates related to cellular peroxidation such as linoleate hydroperoxide and 4-hydroxynon-2-enal or biologically important xenobiotic metabolites such as benzo(a)pyrene-7,8-diol-9,10-oxide.
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PMID:Thymine hydroperoxide, a substrate for rat Se-dependent glutathione peroxidase and glutathione transferase isoenzymes. 377 Jan 98

Hexachlorobenzene (HCB) was administered orally (500 mg/kg d) for 1, 2, 5, or 10d) to sexually mature Japanese quail to compare altered hepatic porphyrin levels with changes that occur in hepatic xenobiotic metabolizing enzymes. Porphyrin levels rapidly increased following the administration of HCB (three times control levels after a single dose of HCB), and birds began to develop porphyria (i.e., porphyrin levels were at least 10 times higher than controls) following 5 d of treatment. Following 10 d of HCB treatment, 3 of 4 treated quail were porphyric. Coincident with the HCB-induced disruption of the heme biosynthetic pathway were increases in various hepatic constituents. Changes included elevation of microsomal protein concentrations and increases in the specific content of cytochrome P-450, in the activities of aryl hydrocarbon hydroxylase (AHH), biphenyl hydroxylase (BPH), ethoxyresorufin-O-deethylase (EROD), and ethoxycoumarin-O-deethylase (ECOD), and in cytosolic and microsomal glutathione S-transferase (GSH-t) levels. In addition, the lambda max of the CO versus CO-reduced absorption spectra of hepatic microsomes from HCB-dosed birds showed a hypsochromic shift of 450 to 448 nm. The activity of NADPH-cytochrome P-450 reductase was increased following 10 d of HCB, and the activity of epoxide hydrolase was increased following 5 d of HCB. Most of these changes occurred with a single HCB treatment, and no further alterations developed in the nature of the response with repetitive dosing. Only weight loss, increased cytochrome P-450 content, and increases in GSH-t activity occurred simultaneously with the induction of porphyria.
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PMID:Hexachlorobenzene-induced porphyria in Japanese quail: changes in microsomal enzymes. 403 90

Although the depletion of hepatic glutathione in male rats following treatment with phorone (diisopropylidene acetone) did not affect the xenobiotic-metabolizing microsomal enzyme system, the metabolic elimination of vinylidene chloride (VDC) from the atmosphere of a closed exposure system was inhibited. However, the hepatotoxicity of VDC was enhanced after GSH-depletion, although no enhancement of VDC-induced in vivo lipid peroxidation was observed. In contrast, GSH depletion had no influence on the metabolic elimination of carbon tetrachloride, but augmented both the hepatotoxic response to and the in vivo lipid peroxidation induced by CCl4. In the case of VDC GSH-depletion hepatoxicity was increased because of a change in the metabolic pathway, resulting in production of intermediates of greater toxicity: lack of GSH in CCl4 treated rats renders membrane phospholipids more susceptible to peroxidative damage.
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PMID:Effect of phorone-induced glutathione depletion on the metabolism and hepatotoxicity of carbon tetrachloride and vinylidene chloride in rats. 407 16

Selenium deficiency and vitamin E deficiency both affect xenobiotic metabolism and toxicity. In addition, selenium deficiency causes changes in the activity of some glutathione-requiring enzymes. We have studied glutathione metabolism in isolated hepatocytes from selenium-deficient, vitamin E-deficient, and control rats. Cell viability, as measured by trypan blue exclusion, was comparable for all groups during the 5-h incubation. Freshly isolated hepatocytes had the same glutathione concentration regardless of diet group. During the incubation, however, the glutathione concentration in selenium-deficient hepatocytes rose to 1.4 times that in control hepatocytes. The selenium-deficient cells also released twice as much glutathione into the incubation medium as did the control cells. Total glutathione (intracellular plus extracellular) in the incubation flask increased from 47.7 +/- 8.9 to 152 +/- 16.5 nmol/10(6) selenium-deficient cells over 5 h compared with an increase from 46.7 +/- 7.1 to 92.0 +/- 17.4 nmol/10(6) control cells and from 47.7 +/- 11.7 to 79.5 +/- 24.9 nmol/10(6) vitamin E-deficient cells. This overall increase in glutathione concentration suggested that glutathione synthesis was accelerated by selenium deficiency. The activity of gamma-glutamylcysteine synthetase was twice as great in selenium-deficient liver supernatant (105,000 X g) as in vitamin E-deficient or control liver supernatant (105,000 X g). Hemoglobin-free perfused livers were used to determine the form of glutathione released and its route. Selenium-deficient livers released 4 times as much GSH into the caval perfusate as did control livers. Plasma glutathione concentration in selenium-deficient rats was found to be 2-fold that in control rats, suggesting that increased GSH synthesis and release is an in vivo phenomenon associated with selenium deficiency.
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PMID:Effect of selenium deficiency and vitamin E deficiency on glutathione metabolism in isolated rat hepatocytes. 612 15

Buthionine sulphoximine (BSO) is an inhibitor of gamma-glutamylcysteine synthetase (gamma-GCS) and, consequently lowers tissue glutathione (GSH) concentrations. In fed male C3H mice, liver and kidney GSH levels were depleted by BSO in a dose dependent manner with maximum effect (35% of initial levels) occurring with doses between 0.8 and 1.6 g/kg, i.p. At these doses maximum effects on gamma-GCS and GSH were observed 2-4 hr after BSO administration; initial gamma-GCS activity and GSH content were restored approximately 16 hr post BSO. BSO, either in vivo or in vitro, had no effect on hepatic microsomal cytochrome P-450 levels, a range of cytochrome P-450 dependent enzyme activities or p-nitrophenol glucuronyl transferase activity. Similarly, BSO had no effect on phenol sulphotransferase and two GSH-transferase activities in the 105,000 g supernatant fraction. BSO had no effect on the duration of hexobarbitone induced narcosis in mice. Consistent with specific inhibition of GSH synthesis, BSO pretreatment of mice decreased the proportion of a 50 mg/kg dose of paracetamol excreted in the urine as GSH-derived conjugates but did not affect paracetamol clearance through the glucuronidation or sulphation pathways. Since BSO does not affect cytochrome P-450 or conjugating enzyme activity, its use as a specific depletor of tissue GSH in the investigation of mechanisms of xenobiotic-induced toxicities is preferable to the standard GSH-depleting agents as these have other enzymic effects.
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PMID:The effects of buthionine sulphoximine (BSO) on glutathione depletion and xenobiotic biotransformation. 614 44

Rat lenses in which all the glutathione has been conjugated with 1-chloro-2,4-dinitrobenzene remain apparently transparent for extended periods of time (up to 24 hours), but are more susceptible to oxidative damage by oxidants such as superoxide anions and hydrogen peroxide. Reduced glutathione has an additional role of detoxification of xenobiotics to form the corresponding mercapturic acids and protection of lens by conjugating the xenobiotics which could be transported out of the lens. The GSH-xenobiotic conjugate transport system is probably shared by GSSG.
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PMID:Lens glutathione depletion of 1-chloro-2,4-dinitrobenzene and oxidative stress. 631 84

Acetaminophen (APAP) disposition was studied in vitro using hepatocytes isolated from rats, hamsters, rabbits, and dogs, species that vary markedly in susceptibility to the hepatotoxicity of this drug. Metabolism was assessed by concurrent measurements of glutathione depletion and protein adduct formation (activation pathway) and of total aqueous metabolite production (detoxication pathways). Cytotoxicity was monitored by cell count and by lactate dehydrogenase (LDH) release to culture medium. In agreement with whole animal studies, hepatocytes from hamsters were very susceptible to APAP-induced toxicity whereas rat and rabbit hepatocytes were resistant. In vivo data were unavailable for the dog, but dog hepatocytes were also relatively resistant. Parameters of APAP metabolism generally correlated with the species susceptibility ranking; however, no single parameter was an ideal index of the sensitivity observed. As predicted by the cytotoxicity data, hamster hepatocytes produced more covalent adducts of APAP, were depleted of GSH more rapidly, and detoxified APAP by formation of polar metabolites at a slower rate than rat hepatocytes. On the other hand, rabbit hepatocytes had no detectable covalent adducts, retained higher amounts of GSH, and metabolized more APAP to polar conjugates than the other species. Dog hepatocytes formed low amounts of both covalent adducts and conjugates. These studies indicate that interspecies comparisons using isolated hepatocytes to study xenobiotic metabolism and the resulting cytotoxicity are feasible, but for a clear understanding of observed differences, it is necessary to study the interrelationships between the toxication and detoxication pathways of metabolism.
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PMID:Metabolism and cytotoxicity of acetaminophen in hepatocytes isolated from resistant and susceptible species. 648 84

Buthionine sulfoximine significantly reduced the hepatic non-protein sulfhydryl (NPSH) content of male B6C3F1 mice within 2 h after intraperitoneal (i.p.) injection. This treatment did not affect the activity of several hepatic microsomal and cytosolic enzymes responsible for xenobiotic metabolism. Pretreatment of mice with buthionine sulfoximine (2 mmol/kg) increased the hepatotoxicity of chloroform, but did not affect the hepatotoxicity of carbon tetrachloride. These findings suggest that buthionine sulfoximine can be a useful agent for studying the role of glutathione (GSH) in hepatic biotransformation of xenobiotics.
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PMID:The effect of buthionine sulfoximine, an inhibitor of glutathione synthesis, on hepatic drug metabolism in the male mouse. 648 15

Microsomal mixed function oxidases (MFO) responsible for phase I xenobiotic metabolism are partially dependent on dietary polyunsaturated fat. The reduced activity of the MFO when fat-free or saturated fat diets are fed has been associated with alterations of microsomal phospholipid fatty acid content. Glutathione S-transferases (GSH-transferases) catalyze phase II conjugation reactions, and are important detoxification pathways for highly reactive phase I-produced intermediates. We hypothesized that activity of membrane-bound, but not soluble, GSH-transferases would be affected by type of dietary fat. Rats were fed diets that contained either 20% coconut oil, 20% corn oil, or a mixture of 18% coconut oil plus 2% corn oil as the sole source of dietary fatty acids. At the end of the 3-week feeding period the activity of both microsomal and soluble fraction GSH-transferases of rat liver was determined. The original hypothesis that dietary fat type would alter membrane-bound transferase activity was not supported by the results since GSH-transferase activity in the microsomal fraction was not affected. However, feeding 20% coconut oil produced a 25 to 40% decrease in soluble transferase activity compared to corn oil feeding. The Michaelis constant (Km) for soluble GSH-transferase was threefold higher when the diet was devoid of polyunsaturated fat. Ultrafiltration of the soluble fraction to remove compounds with molecular weights below 50,000 did not eliminate the differences in transferase activity due to dietary fat. Separation of the soluble transferases by fast protein liquid chromatography indicated that quantities of the various transferases were affected equally by type of dietary fat. The results indicate that type of dietary fat may be important in determining the ability to detoxify carcinogens or other toxins that are conjugated with glutathione.
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PMID:Effects of dietary saturated or polyunsaturated fat on hepatic glutathione S-transferase activity. 651 Feb 37


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