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)

The in vitro conversion of (+)-3,4-methylenedioxymethamphetamine and (-)-3,4-methylenedioxymethamphetamine to the corresponding catecholamine, 3,4-dihydroxymethamphetamine (N-methyl-alpha-methyldopamine), by rat liver microsomes was examined. Metabolite formation was monitored after short-term incubations using high-performance liquid chromatography-electrochemical detection to determine concentrations of the catecholamine. The formation of N-methyl-alpha-methyldopamine exhibited enantioselectivity and levels were significantly higher after incubation of the (+)-isomer. The reaction appears to be cytochrome P-450 dependent as it was sensitive to SKF 525A and carbon monoxide. The catecholamine was unstable and was metabolized rapidly to a compound capable of forming an adduct with glutathione (GSH) and other thiol compounds. This second oxidation did not appear to be cytochrome P-450-dependent but required NADPH and microsomal protein. Catecholamine oxidation was inhibited by superoxide dismutase and by reducing agents. The same catecholamine oxidation product, characterized as the GSH adduct, could be generated by a xanthine-xanthine oxidase mixture and by tyrosinase. Mass spectral data showed that it was a 1:1 amine GSH adduct. These results indicate that MDMA is oxidized by cytochrome P-450 to the catechol and the catecholamine oxidized by superoxide to a quinone to which GSH or other thiol functions add. The formation of this quinone and its thiol adducts may account for some of the irreversible actions of this compound on serotonergic neurons.
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PMID:Metabolism of methylenedioxymethamphetamine: formation of dihydroxymethamphetamine and a quinone identified as its glutathione adduct. 197 41

1. Rats were exposed to m-xylene (300 ppm) and methyl ethyl ketone (MEK, 600 ppm) vapour, separately and in combination. 2. Repeated exposures to m-xylene enhanced liver drug-metabolizing capacity, whereas MEK showed no effects. After mixed exposure the cytochrome P-450-dependent monooxygenase activities were additively or synergistically induced. 3. In the presence of MEK the overall metabolism of xylene was strongly inhibited both after single and repeated exposures, an effect accompanied by elevation of xylene concentration in blood (18-29%) and fat (25-32%). 4. The 24-h excretion of the urine metabolites of m-xylene was decreased by 22-24% in mixed exposures: the excretion of methylhippuric acid was decreased (29%), but that of 2,4-dimethylphenol increased (9-35%). 5. After repeated inhalation exposures the excretion of xylene metabolites in urine was consistently higher, whereas the concentrations of xylene in fat (but not the concentration of MEK) were lower than after a single treatment, conceivably due to accelerated metabolic clearance of xylene. 6. Thioether excretion in urine was enhanced in xylene-treated rats (7-13-fold), but was not influenced by the induced changes in the metabolism of xylene. Xylene inhalation caused liver GSH to decrease slightly (10%), as did inhalation of MEK, but the latter did not enhance the excretion of thioethers. 7. MEK is a potent inhibitor of the side-chain oxidation of m-xylene producing methylhippuric acid, but not of its ring oxidation to 2,4-dimethylphenol, and exhibits a synergistic inducing effect on liver enzymes responsible for the oxidation of m-xylene. The increased ring oxidation of m-xylene was not associated with increased production of reactive metabolites indicated by GSH-depletion or thioether formation.
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PMID:Metabolic interaction and disposition of methyl ethyl ketone and m-xylene in rats at single and repeated inhalation exposures. 200 67

The pyrimidine precursor orotic acid (OA) is a constituent of dairy products and therapeutic drugs. Several recent publications point towards a tumor promoting activity of OA in rat liver. An increased production of reactive oxygen has been discussed as a possible mechanism, leading to lipid peroxidation and DNA single strand breaks. In view of contradictory results, this postulated prooxidative action of OA was reexamined with new experimental techniques. Weanling Sprague-Dawley rats were fed 1% OA in different diets for 4-35 days. The NADPH-mediated lipid peroxidation in liver homogenate and microsomes was determined in vitro by analysis of low-level chemiluminescence (CL) and the strongly correlated formation of malondialdehyde (MDA). In no case did treatment with OA result in an increase of lipid peroxidation in vitro nor did such treatment enhance the generation of reactive oxygen as measured by lucigenin CL. In accordance, the total cytochrome P-450 content as well as the activity of individual P-450 isoenzymes were unchanged. Treatment with OA did not elevate the MDA content of fresh liver homogenate when butylated hydroxytoluene (BHT) was present in the test system. However, when the antioxidant was omitted, increased levels of thiobarbituric acid reactive material were found which correlated with the triglyceride content. This could explain some published data that have been taken as indication for a prooxidative action of OA. Evidence against an increased lipid peroxidation in vivo is given by the analysis of ethane exhalation. Furthermore, no increase in DNA single strand breaks by OA treatment could be observed by the alkaline elution technique. These results do not support the hypothesis of a prooxidative activity of OA. The observed reversible decrease of the GSH/GSSG ratio is assumed to result from the reduced size of the phosphopyridine nucleotide pool due to purine deficiency and an increased consumption of NADPH by the enhanced reductive degradation of pyrimidines.
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PMID:Effect of orotic acid on the generation of reactive oxygen and on lipid peroxidation in rat liver. 201 18

The occurrence and persistence of DNA fragmentation, as detected by the alkaline elution technique, have been studied in rats treated with single oral doses of the hepatocarcinogen 2-nitropropane (2-NP). A progressive increase of liver DNA fragmentation was observed at doses ranging from 0.5 to 8 mmol/kg; single strand breaks reached the maximum frequency 6 h after administration, and were partially reduced after 36 h. In contrast, DNA fragmentation was absent in lung, kidney, bone marrow and brain of rats given 8 mmol/kg. The role of cytochrome P-450 in the activation of 2-NP is indicated by the increase of liver DNA damage in rats pretreated with phenobarbital or beta-naphtoflavone, and by its reduction produced by methoxsalen. Both administration of GSH and GSH depletion did not result in clearcut modifications of the genotoxic effect of 2-NP for the liver.
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PMID:DNA fragmentation by 2-nitropropane in rat tissues, and effects of the modulation of biotransformation processes. 202 80

Pulmonary toxicity of naphthalene (NAP), 2-methylnaphthalene (2-MN), 2-isopropylnaphthalene (2-IPN) and 2,6-diisopropylnaphthalene (2,6-DIPN) was studied in mice. Twenty four h after the intraperitoneal (i.p.) administration of NAP (200 mg/kg (1.6 mmol] or 2-MN (400 mg/kg (2.8 mmol], pulmonary damage was detected. Prior treatment with diethyl maleate resulted in enhancement of NAP and 2-MN-induced bronchiolar damage. In contrast to the effects of NAP and 2-MN, injections of 2-IPN (3000 mg (17.6 mmol)/kg) and 2,6-DIPN (3000 mg (14.2 mmol)/kg) did not cause detectable pulmonary damage. Injections of NAP and 2-MN caused considerable depletion of pulmonary reduced glutathione (GSH), while injections of 2-IPN and 2,6-DIPN caused only a slight depletion. There were general decreases in the binding of the compounds to lung slices with increasing number of carbons of the alkyl substituent. Pretreatment with a cytochrome P-450 inducer (beta-naphthoflavone) increased the binding of NAP, 2-MN, and 2-IPN to lung slices. Treatments with NAP, 2-MN, 2-IPN and 2,6-DIPN did not affect the lipid peroxidation or phospholipid contents in the lung. These results suggest that the difference in pulmonary toxicity among NAP, 2-MN, 2-IPN, and 2,6-DIPN may be dependent on the ability of these compounds to irreversibly bind to lung tissue.
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PMID:Alkylnaphthalene. XI. Pulmonary toxicity of naphthalene, 2-methylnaphthalene, and isopropylnaphthalenes in mice. 208 98

Ten compounds with a wide variety of structures, which decreased hepatic glutachione (GSH) content at an early time period after their administration, simultaneously increased hepatic heme oxygenase, ornithine decarboxylase (ODC) and S-adenosylmethionine decarboxylase (SAMDC) activities in rats. The compounds examined were four alpha, beta-unsaturated carbonyl compounds, two prototype substrates for GSH transferase(s), one epoxide, two isothiocyanates, and an indicator of hepatic function test. Time course studies with 1-chloro-2,4-dinitrobenzene (CDNB) and 1,2-dichloro-4-nitrobenzene (DCNB), which are prototype substrates for GSH transferases, showed that there was an inverse relationship between the early depletion of hepatic GSH content and induction of heme oxygenase, ODC and SAMDC together with a decrease in cytochrome P-450 content and an increase in putrescine content. Buthionine sulfoximine (BSO), an inhibitor of GSH synthesis, also increased heme oxygenase and SAMDC activities, but not ODC, and it tended to enhance the induction of the enzymes evoked by diethyl maleate (DEM), phorone and CDNB with the sustained depletion of GSH content. In contrast, GSH treatment inhibited DEM-, phorone-, and CDNB-mediated induction of these enzymes and the early depletion of GSH content. N-Acetylcysteine failed to inhibit DEM- and phorone-mediated induction of these enzymes and the early depletion of GSH content, while it inhibited somewhat these changes produced by CDNB. The findings suggest that the early depletion of hepatic GSH content is prerequisite for and plays a role in the induction of heme oxygenase, ODC and SAMDC.
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PMID:Possible role of glutathione depletion in the induction of rate-limiting enzymes involved in heme degradation and polyamine biosynthesis in the liver of rats. 209 3

We have developed new co-cultures of continuous cell lines 3T3 (clone A31) and C3H/10T1/2 (clone 8) with hepatocytes as an alternative to co-cultures with noncontinuous epithelial cells. In this biological system we studied in detail the expression of the hepatic biotransformation system. After 7 d in culture, total cytochrome P-450 content and the monooxygenase activities aryl hydrocarbon hydroxylase and 7-ethoxycoumarin o-deethylase still maintained about 30% of their initial value, whereas in pure cultured hepatocytes these activities were undetectable. A significant response to induction by methylcholanthrene and phenobarbital of monooxygenase activities was observed in co-cultures for 7 d. NADPH-cytochrome c reductase activity remained unchanged for at least 7 d in co-cultured hepatocytes, whereas in pure cultures this activity was reduced to about 75% of the initial value after only 24 h. Finally, the activity of the conjugating enzymes UDP-Gt and GSH-t was maintained at nearly the initial levels during the complete period of study. The easy handling of continuous cell lines and the maintenance of the biotransformation system of hepatocytes in co-culture make this approach simpler and easier to standardize.
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PMID:Drug metabolizing enzymes in rat hepatocytes co-cultured with cell lines. 212 8

The conjugation of the prototype dihaloalkane ethylene dibromide (EDB) with glutathione (GSH) yields S-(2-bromoethyl)GSH, which gives rise to S-[2-(N7-guanyl)ethyl]GSH as the major DNA adduct (greater than or equal to 95%). All reaction steps have SN2 character. Another minor DNA and RNA adduct is S-[2-(N1-adenyl)ethyl]GSH, formed in vitro and in vivo. These adducts have similar half-lives in vivo. Enhancement of GSH conjugation or inhibition of cytochrome P-450 IIE1 oxidation enhances DNA adduct levels in vivo and GSH depletion lowers levels. The mercapturic acid N-acetyl-S-[2-(N7-guanyl)ethyl]cysteine is excreted in urine and may find use as a biomarker. A series of compounds of the general structure RSCH2CH2Cl has been used to alkylate Salmonella typhimurium TA100. The ratio of (guanyl) base-pair mutations to N7-guanyl adducts varies dramatically, with S-(2-chloroethyl)GSH apparently producing the most potent guanyl adduct. This mutagenicity is not due to SOS response or alkylation specificity. Physical studies with modified oligonucleotides indicate that the N7-guanyl substitution weakens G-C pairing but does not in itself alter the selectivity of pairing to C in an isolated oligomer.
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PMID:DNA-glutathione adducts derived from vic-dihaloalkanes: mechanisms of mutagenesis. 213 69

The hepatotoxicity of CCl4 is mediated through its initial reduction by cytochrome P-450 to the CCl3.radical. This radical then damages important metabolic systems such as the ATP-dependent microsomal Ca2+ pump. Previous studies from our laboratory on isolated microsomes have shown that NADPH in the absence of toxic agents inhibits this pump. We have now found in in vitro incubations that CCl4 (0.5-2.5 mM) enhanced the NADPH-dependent inhibition of Ca2+ uptake from 28% without CCl4 to a maximum of 68%. These concentrations are in the range found in the livers and blood of lethally intoxicated animals (Dambrauskas, T., and Cornish, H. H. (1970) Toxicol. Appl. Pharmacol. 17, 83-97; Long, R.M., and Moore, L. (1988) Toxicol. Appl. Pharmacol. 92, 295-306) and are toxic to cultured hepatocytes (Long, R. M., and Moore, L. (1988) Toxicol. Appl. Pharmacol. 92, 295-306). The inhibition of Ca2+ uptake was due both to a decrease in the Ca2(+)-dependent ATPase and to an enhanced release of Ca2+ from the microsomes. The NADPH-dependent CCl4 inhibition was greater under N2 and was totally prevented by CO. GSH (1-10 mM) added during the incubation with CCl4 prevented the inhibition. This protection was also seen when the incubations were performed under nitrogen. When samples were preincubated with CCl4, the CCl4 metabolism was stopped, and then the Ca2+ uptake was determined; GSH reversed the CCl4 inhibition of Ca2+ uptake. This reversal showed saturation kinetics for GSH with two Km values of 0.315 and 93 microM when both the preincubation and the Ca2+ uptake were performed under air, and 0.512 and 31 microM when both were performed under nitrogen. Cysteine did not prevent the NADPH-dependent CCl4 inhibition of Ca2+ uptake. CCl4 increased lipid peroxidation in air, but no lipid peroxidation was seen under nitrogen. Lipid peroxidation was only modestly reversed by GSH. GSH did not remove 14C bound to samples preincubated with the 14CCl4. Although EDTA (100 microM) decreased the CCl4 inhibition, the metal-complexing agents deferoxamine (100 microM) and diethyldithiocarbamate (100 microM) had no effect on the inhibition of the pump. Similarly, the reactive oxygen scavengers catalase (65 micrograms/ml), superoxide dismutase (15 micrograms/ml), mannitol (10 mM), and dimethyl sulfoxide (50 mM) also had no effect. Our results suggest that the initial toxicity of CCl4 for the Ca2+ pump results from the metabolism of CCl4 to the CCl3. radical. This radical then directly oxidizes the Ca2+ pump, leading to decreased Ca2+ uptake.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:The in vitro NADPH-dependent inhibition by CCl4 of the ATP-dependent calcium uptake of hepatic microsomes from male rats. Studies on the mechanism of the inactivation of the hepatic microsomal calcium pump by the CCl3.radical. 214 Mar 58

In hepatic microsomes one or more isozymes of cytochrome P-450 inhibits the ATP-dependent Ca2+ pump. This inhibition is reversible by GSH and appears to be due to a direct oxidation of the pump proteins by the oxygenated cytochrome. To determine which isozyme mediates this inhibition, we have examined the effect of various substrates and inhibitors on the NADPH inhibition of Ca2+ uptake. We find that aminopyrine, benzphetamine and SKF-525A reverse this inhibition while a number of other substrates do not. This pattern suggests that a previously unreported isozyme of cytochrome P-450 mediates the Ca2+ pump inhibition.
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PMID:The effect of substrates and inhibitors of cytochrome P-450 on the NADPH inhibition of the ATP-dependent, hepatic, microsomal calcium pump. 214 93


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