Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:2.5.1.18 (glutathione S-transferase)
22,582 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Hepatocytes were isolated from adult male and female rats and maintained in monolayer culture for up to 24 hr. The degree of preservation of representative phase I and phase II xenobiotic biotransformation enzymes was studied in these cells immediately after isolation, after attachment in culture, and after 24 hr in culture. Regarding phase I pathways, hepatocytes during 24 hr lost 50% of cytochrome P-450, but maintained high mixed function oxidase activities; 75% of aryl hydrocarbon hydroxylase and 65% of benzphetamine demethylase activities were preserved in hepatocytes from males, whereas in hepatocytes from females 70 and 50% of these activities, respectively, were maintained. Of phase II pathways, glutathione transferase activity after 24 hr, tested toward 1,2-dichloro-4-nitrobenzene as substrate, was diminished in male hepatocytes to 20% of the initial liver activity and in female cells, to 35%, whereas the activity tested toward 1-chloro-2,4-dinitrobenzene as substrate was stable. UDP-glucuronosyltransferase activities, tested toward p-nitrophenol and phenolphthalein as substrates, were slightly increased during 24 hr of culture of hepatocytes to levels higher than in liver before perfusion. The level of UDP-glucuronic acid, the endogenous substrate for the enzyme, was reduced after isolation to only 6% of the initial liver value, and then increased during culture to a level approximately 60% of normal. Thus, the changes in xenobiotic biotransformation enzymes and associated constituents in cultured hepatocytes were not uniform, although biotransformation capability remained reasonably intact.
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PMID:Activities of several phase I and phase II xenobiotic biotransformation enzymes in cultured hepatocytes from male and female rats. 392 82

After administration of beta-naphthoflavone and Clophen A50 to juvenile rainbow trout, activities of hepatic cytochrome P-450-dependent deethylation of 7-ethoxyresorufin was increased 172- and 49-fold, respectively. Glutathione transferase activity towards 1-chloro 2,4 dinitrobenzene and UDP glucuronosyltransferase activities towards p-nitrophenol, 1-naphthol and testosterone were increased 1.4 to 3.0-fold by beta-naphthoflavone or Clophen A50. However, significant increases of the rate of glucuronidation of 1-naphthol by Clophen A50 and of testosterone by both Clophen A50 and beta-naphthoflavone were only determined when the activities were measured in digitonin activated microsomes. Epoxide hydrolase activity was not affected by beta-naphthoflavone or Clophen A50. The time course of induction of the various xenobiotic metabolizing enzymes exhibited different patterns. 7-Ethoxyresorufin-O-deethylase activity reached peak values 3 and 7 days after the administration of beta-naphthoflavone and Clophen A50, respectively. The rate of induction of glutathione transferase activity and UDP glucuronosyltransferase activities towards p-nitrophenol and 1-naphthol were relatively slow and did not reach distinct peak levels. These activities were still on maximum levels 4-6 weeks after the treatment. Glucuronidation of testosterone reached peak values 1 week after treatment with both beta-naphthoflavone and Clophen A50. The dissimilar patterns of induction of the cytochrome P-450-dependent activities and the various conjugation activities may indicate that these xenobiotic metabolizing enzymes are differently regulated in the rainbow trout liver.
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PMID:Differential induction of cytochrome P-450-dependent monooxygenase, epoxide hydrolase, glutathione transferase and UDP glucuronosyl transferase activities in the liver of the rainbow trout by beta-naphthoflavone or Clophen A50. 392 91

Several communications pertaining to research on human fetal drug biotransformation have appeared in the literature in the past 3 to 4 years (Aranda et al. 1979; Cresteil et al. 1982; Pacifici et al. 1981; Pacifici and Rane 1982, 1983; Schroeter and Amon 1983). In general, research in this area has produced no major recent surprises, but it has confirmed, extended, and supported the earliest findings through those of the mid-1970s and has served to expand our understanding of these important systems. The important aspects of our current knowledge may be summarized very briefly as follows: Each of the major drug metabolic reactions (oxidations, reductions, hydrolyses, and conjugations) can be catalyzed at generally low rates by enzymes present in human fetal and placental tissues. Reaction rates appear, in general, to increase with advancing gestational age. Placental xenobiotic-biotransforming monooxygenases display a high sensitivity to the effects of MC-type (methylcholanthrene) but not PB-type (phenobarbital) inducing agents during the later stages of gestation. Responsivity is minimal during early gestation. Monooxygenases in other fetal tissues (liver, adrenal gland, etc.) appear to respond minimally to inducing agents, at least during the earlier stages of gestation. Glucuronyl transferase activities appear to be very low in all fetal and placental tissues. Epoxide hydrolase, glutathione S-transferase, and sulfotransferase (and perhaps others) activities can be relatively high in prenatal primate hepatic tissues but, at present, are difficult to predict. Some of these may respond to environmental inducers in situ, but solid evidence for this is still lacking.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Biotransformations of drugs and foreign chemicals in the human fetal-placental unit. 393 63

Cutaneous xenobiotic metabolizing enzymes including aryl hydrocarbon hydroxylase (AHH), 7-ethoxycoumarin O-deethylase (ECD), epoxide hydrolase (EH) and glutathione S-transferase (GST) activities were examined in SKH hairless mice chronically irradiated with UVB to induce squamous cell carcinoma (SCC). Enzyme activities in irradiated tumor-bearing skin were compared to those present in the skin of nonirradiated control animals as well as in unirradiated non-tumor bearing skin sites of the SCC-bearing mice. The inducibility of skin AHH and ECD in each set of animals was assessed following a single topical application of coal tar (1 ml/100 g). Enzyme-mediated binding of [3H]benzo(a)pyrene (BP) and its metabolite 7 beta,8 alpha-dihydroxy-9 alpha,10 alpha-epoxy-7,8,9,10-tetrahydrobenzo(a)pyrene (BPDE-I) to epidermal DNA was also evaluated. Basal AHH and ECD activities in microsomes from UVB-irradiated SCC-bearing dorsal skin were 4.6- and 4.8-fold lower than those in dorsal skin of nonirradiated control animals. Enzyme activities in non-tumor bearing ventral skin from the UVB-irradiated SCC-bearing mice also were 2.2 to 2.8-fold lower as compared to activities in the nonirradiated control animals. The reduction in AHH activity paralleled the levels of enzyme-mediated binding of radiolabeled BP metabolites and of BPDE-I to epidermal DNA. GST activity was found to be increased (173%) in non-tumor bearing ventral skin of UVB-irradiated mice whereas no difference in activity between SCC-bearing dorsal skin and dorsal skin of control animals could be detected. EH activity was unchanged in each group of animals. Treatment with topically applied coal tar resulted in higher inducibility of AHH and ECD in both SCC-bearing (13-fold) as well as in non-tumor skin sites (6-fold) of UVB-irradiated mice than in skin of control animals (3-fold). Coal tar application also increased the covalent binding of [3H]BP and of the metabolite BPDE-I to skin DNA. This was greater in SCC-bearing dorsal skin (119-129%) than in nonirradiated skin of control animals (48-62%). Our studies suggest that the metabolism of BP by cutaneous cytochrome P-450 dependent monooxygenases is impaired in skin of mice irradiated chronically with UVB. The higher inducibility of these monooxygenases by topically applied coal tar and the enhancement of the associated enzyme-mediated covalent binding of BP metabolites and BPDE-I to epidermal DNA indicate that repetitive exposure of mammalian skin to UVB radiation can profoundly alter the activity and the inducibility of drug and carcinogen metabolizing enzymes.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Altered patterns of cutaneous xenobiotic metabolism in UVB-induced squamous cell carcinoma in SKH-1 hairless mice. 399 3

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

Young male C57BL mice were exposed nose-only to cigarette smoke 20 min/day for 8 weeks while maintained on diets containing 0, 5, and 100 ppm of vitamin E. Smoking had no effect on hepatic aryl hydrocarbon hydroxylase (AHH), UDP-glucuronyltransferase, glutathione S-transferase, parathion desulfurase, or parathion esterase activity. Lung AHH activity was increased in all smoke-exposed mice, although the increase was significantly less in animals maintained on the vitamin E-free diet. All mice on the vitamin E-free diet showed reduced lung AHH activity and increased hepatic lipid peroxidation. No other biotransformations tested were significantly altered by varying vitamin E concentrations alone or in combination with cigarette smoke. For all vitamin E diets, both the smoke-exposed and sham-treated mice gained significantly less weight than the control animals. This effect was attributed to stress induced by restraint of the animals within the smoking apparatus. The results of these experiments show that both cigarette smoke and vitamin E-deficient diets may affect xenobiotic metabolism but that the combination does not appear to alter markedly their individual effects or to induce ones not previously observed.
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PMID:Effects of cigarette smoke and dietary vitamin E levels on selected lung and hepatic biotransformation enzymes in mice. 406 31

The postnatal development of microsomal aryl hydrocarbon hydroxylase (AHH), 7-ethoxycoumarin O-deethylase (ECD), epoxide hydrolase (EH) [benzo(a)pyrene (BP)-4,5-oxide as substrate], and cytosolic glutathione S-transferase (GST) was studied in skin of Sprague-Dawley rats. Animals were treated with skin application of 3-methylcholanthrene (MCA) (40 mg/kg, 24 hr before sacrifice) or acetone. Enzyme activities were detected in animals of all ages. AHH and ECD in control rats showed slight age-dependent variation. Age-dependent differences in inducibility of skin AHH and ECD by topically applied MCA were observed. At 4, 6, 10, 18, 24, 32, and 55 days of age, the inducibility of AHH was 11, 18, 18, 19, 20, 23, and 21-fold, respectively. A similar pattern was observed for ECD. EH activity in 24-day-old skin was twice that in 4-day-old animals. GST activity remained constant throughout maturation. EH and GST activities were not altered by MCA. BP metabolism was studied in control and MCA-induced neonatal (4-day-old), young (18-day-old), and adult (55-day-old) animals. MCA treatment increased the rate of metabolism of BP at all ages studied. Higher rates of BP metabolism occurred in adult skin as compared to younger or neonatal rat skin. Inducibility of trans-7,8-diol formation by topically applied MCA was highest in the adult (19-fold) rat skin as compared to younger (12-fold) or neonatal rat skin (10-fold). These studies suggest that xenobiotic metabolism in skin of rats undergoes variable changes during aging which could exert some influence on pharmacologic responses to topically applied agents in cutaneous tissue.
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PMID:Age-related changes in benzo(a)pyrene metabolism and epoxide-metabolizing enzyme activities in rat skin. 614 Jan 40

Homogenate preparations from fresh livers of cattle, sheep, swine and rats were assayed for microsomal cytochrome P-450 content, for mixed-function oxidase activities and for a wide array of conjugative activities using numerous xenobiotic substrates. Results show that hepatic enzymatic capabilities toward xenobiotics do not parallel phylogenetic classifications, thus strengthening the view that most of the comparative data available at present is more descriptive than predictive of relationships among species. Livestock species differed widely from rats in having lower activities of benzo(alpha)pyrene hydroxylase, glutathione S-transferase and acetyltransferase toward isoniazid and sulfamethazine and UDP-glucuronosyl-transferase toward bilirubin. Acetyltransferase activities toward beta-naphthylamine and 2-aminofluorene were not detected in livers of livestock species studied. Cattle livers were remarkably high in activities of styrene oxide hydrolase, ethoxyresorufin O-deethylase, 2-naphthol sulfotransferase and p-aminobenzoic acid acetyltransferase; but notably low in activity of glutathione-S-transferase toward sulfobromophthalein and 1,2-dichloro-4-nitrobenzene. Swine livers had low activity of glutathione-S-transferase toward four of six substrates and low acetyltransferase activity toward four of five substrates. Sheep livers generally were higher than cattle livers in sulfo- and UDP-glucuronsyltransferase activities and lower in acetyl- and glutathionyl-S-transferase. Findings emphasize the risk of error in extra-polations among species and in extrapolations among substrates.
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PMID:Oxidative and conjugative metabolism of xenobiotics by livers of cattle, sheep, swine and rats. 642 1

The present study was designed to prepare and characterize subcellular fractions from the trunk kidney of the Northern pike (Esox lucius), with special emphasis on the preparation of a microsomal fraction suitable for studying xenobiotic metabolism. The purity of the different fractions obtained by differential centrifugation, as well as the recovery of different organelles, was determined using both enzyme markers and morphological examination with the electron microscope. Finally, the subcellular distributions of several drug-metabolizing enzymes (NADPH-cytochrome c reductase, NADH-ferricyanide reductase, glutathione transferase, epoxide hydrolase) were determined. With the exception of NADPH-cytochrome c reductase, the subcellular distributions obtained here for drug metabolizing and marker enzymes closely resembled those reported for rat liver. NADPH-cytochrome c reductase was apparently partially solubilized here from microsomal vesicles by an endogenous protease, which reduced its usefulness as a marker enzyme and raises questions concerning the measurement of activities catalyzed by the cytochrome P-450 system in these subfractions. In other respects the microsomes and supernatant fraction prepared here from the trunk kidney of the pike seem to be as well suited for investigations of drug metabolism as are the corresponding fractions from rat and pike liver.
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PMID:Preparation and characterization of subcellular fractions suitable for studies of drug metabolism from the trunk kidney of the Northern pike (Esox lucius) and assay of certain enzymes of xenobiotic metabolism in these subfractions. 643 81

Using antibody directed against glutathione S-transferase B (YaYc heterodimer) and glutathione S-transferases A and C (Yb homodimers), we have purified the corresponding mRNAs by polysome immunoprecipitation. These mRNAs have been utilized to synthesize high specific activity cDNA probes which have been used to screen a cDNA library constructed from RNA fractions enriched in the various transferase mRNAs. Two clones which have been identified, pGTB38 and pGTA/C36, are complementary to the Ya/Yc mRNAs and Yb mRNAs, respectively. These clones have been utilized to determine that the Ya/Yc mRNAs and Yb mRNA(s) are elevated coordinately in response to xenobiotic treatment; however, their maximal level of induction is markedly different. Based upon the size of the mRNA specific for the Ya/Yc and Yb subunits, as well as the lack of homology between pGTB38 and pGTA/C36, we conclude that transferase B and transferases A and C are encoded for by distinct genes.
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PMID:Regulation of glutathione S-transferase mRNAs by phenobarbital and 3-methylcholanthrene: analysis using cDNA probes. 654 28


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