Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:2.5.1.18 (glutathione S-transferase)
 22,582 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Drug metabolizing enzymes, particularly those involved in the metabolism of carcinogenic chemicals, were characterized in cultured human keratinocytes. Using immunoblotting experiments, we analysed the expression of phase I enzymes, cytochrome P4501A1 (CYP1A1) and NADPH reductase, and phase II enzymes, phenol UDP-glucuronosyltransferase (UGT) and glutathione S-transferase (GST) isoform pi, in the presence of either classical inducers (i.e. 3-methylcholanthrene, dimethylbenz[a]anthracene, phenobarbital, and clofibrate) or all-trans retinoic acid (RA). This study has shown that the expression of CYP1A1 and UGT is concomitantly induced by 3-methylcholanthrene, dimethylbenz[a]anthracene, and RA, and that of NADPH reductase is only enhanced by phenobarbital and RA. In contrast, the expression of GST pi was not affected by the inducers. Using the reverse transcriptase-polymerase chain reaction, we have demonstrated that the effects of 3-methylcholanthrene, dimethylbenz[a]anthracene and RA on CYP1A1 expression correlate with an increase of CYP1A1 mRNA level. Our results indicate that, with the exception of clofibrate, xenobiotics and RA differentially modulate the expression of drug metabolizing enzymes.
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PMID:Constitutive and inducible expression of drug metabolizing enzymes in cultured human keratinocytes. 775 27

Variations in the total capacity of the rat ovary to metabolize xenobiotics during different phases of the estrous cycle were studied. The level of the conjugating enzymes, phenol UDP-glucuronosyltransferase (pUDPGT; EC 2.4.1.17), phenol sulfotransferase (pST; EC 2.8.2.1) and glutathione transferases (EC 2.5.1.18) was determined in the ovary and compared with the corresponding hepatic activities. In addition, catalase (EC 1.11.1.6) and NAD(P)H: quinone oxidoreductase (EC 1.6.99.2) two other detoxifying enzymes, were assayed. In order to study the hormonal influences on detoxifying enzymes, mature rats were characterized with respect to their stage in the estrous cycle. Immature rats were treated with pregnant mare's serum gonadotropin (PMSG) for 2 or 3 days to enrich the ovaries in preovulatory follicles or corpora lutea, respectively. The present study demonstrates that ovarian pUDPGT and pST activities are increased 936% and 175%, respectively, in ovaries enriched in corpora lutea compared to ovaries from untreated immature rats. Increases in these activities in mature rats during the metestrous stage of the estrous cycle compared to the proestrous stage were also noted. In the liver pUDPGT activity is increased significantly (1.6-fold) in immature rats with ovaries enriched in preovulatory follicles compared to untreated rats. Both ovarian pST and pUDPGT activities increased in mature rats treated with PMSG ("hyperstimulated"), while in the liver only pST was increased by such treatment. Ovarian glutathione transferase activity proved not to be dependent on the hormonal fluctuations associated with the estrous cycle. However, in the liver of mature rats treated with PMSG, this activity increased 2-fold compared to the untreated immature rats. The catalase activity found in the ovarian mitochondrial fraction was approx. 10-fold higher than in the cytosolic fraction, independent of the hormonal status. Moreover, we found a significant 1.4-fold increase in peroxisomal catalase activity in the mitochondrial fraction of immature rats treated with PMSG, both when enriched in preovulatory follicles and in corpora lutea. In the liver cytosolic catalase activity decreased several-fold in immature rats following PMSG treatment. We did not find any variations in ovarian NAD(P)H: quinone oxidoreductase activity during the estrous cycle, whereas in the liver this activity decreased in the luteal phase, as it did in mature rats treated with PMSG. From this study and earlier investigations in our laboratory, we conclude that cyclic variations due to hormones of the estrous cycle of the major 7,12-dimethylbenz(a)anthracene (DMBA)-metabolizing phase I enzymes in the ovary are not accompanied by increases in the activities of the corresponding phase II enzymes.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Hormonal influences of detoxication in the rat ovary on enzymes in comparison with the liver. 787 55

The activities of several different phase I and phase II drug-metabolizing enzymes were measured in freshly isolated oval cells from rats fed a choline-deficient/DL-ethionine-supplemented diet for 6 weeks and also in vitro in the established oval cell line OC/CDE 6. No cytochrome P450 was spectrophotometrically measurable in both preparations and two cytochrome P450-dependent monoxygenase activities, aminopyrine N-demethylase and ethoxyresorufin O-deethylase, could not be detected in the oval cells of both sources. However, cytosolic glutathione transferase, microsomal epoxide hydrolase and UDP-glucuronosyltransferase activities were clearly measurable in oval cells. Similar enzyme activities were found in freshly isolated and cultured oval cells. The highest activities of these three enzymes were detected during the exponential growth phase of the cultured cells; thereafter the activities decreased until the cells reached confluency. Changes in phenol UDP-glucuronosyltransferase (UGT1A1) mRNA levels paralleled the variations in UDP-glucuronosyltransferase activity, i.e. they were high in exponentially growing oval cells and low in confluent cell cultures. Taking into account that oval cells are able to proliferate in the livers of rats continuously fed a choline-deficient/DL-ethionine-supplemented diet and that none of the analyzed drug metabolizing enzymes are involved in the activation or detoxication of DL-ethionine, the described pattern might be part of a more general, nonspecific, protection mechanism enabling these cells to overcome the cytotoxic effects of a variety of carcinogens and to proliferate even in their presence. Furthermore, the expression of microsomal epoxide hydrolase, cytosolic glutathione transferase and UDP-glucuronosyltransferase appears to depend on the proliferative status of the cells.
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PMID:Drug-metabolizing enzyme activities in freshly isolated oval cells and in an established oval cell line from carcinogen-fed rats. 807 23

Rats were treated with nitrogen-containing phenanthrene (3,4-, 5,6-, or 7,8-benzoquinoline) or anthracene (acridine or quinacrine) derivatives at a dose of 75 mg/kg, daily for 3 days. The hepatic drug metabolizing enzyme response ranged from no induction (quinacrine) through low (5,6-benzoquinoline), intermediate (acridine), and high (3,4-benzoquinoline) magnitude increases of only phase II enzymes, to induction of both phase I and phase II enzymes (7,8-benzoquinoline). The phase I enzyme response of 7,8-benzoquinoline was an induction of CYP1A. All three benzoquinolines, but neither anthracene derivative, elevated NAD(P)H quinone oxidoreductase activity. A similar pattern but of lesser magnitude was seen with glutathione S-transferase activity. 3,4-Benzoquinoline was the only agent to significantly increase microsomal epoxide hydrolase activity (2,3-fold). Both 3,4- and 7,8-benzoquinoline increased UDP-glucuronosyltransferase activity toward 4-nitrophenol (40% and 70%, respectively), but only the 3,4-isomer increased activity toward morphine (75%), diclofenac (75%), and testosterone (23%), and only the 7,8-isomer increased activity toward chloramphenicol (105%). 3,4-Benzoquinoline elevated the hepatic mRNA concentration of UGT2B1 but not UGT1*6. Acridine treatment increased UDP-glucuronosyltransferase activity toward morphine (47%), 1-naphthol (28%), testosterone (19%), and estrone (19%). Quinacrine failed to elevate any UDP-glucuronosyltransferase activity and depressed activities toward testosterone and estrone by 20%. This study shows that some tricyclic aromatic compounds containing a single heterocyclic nitrogen atom have the potential for use as chemoprotective agents based upon their ability to selectively induce only phase II enzymes.
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PMID:Drug metabolizing enzyme induction by benzoquinolines, acridine, and quinacrine; tricyclic aromatic molecules containing a single heterocyclic nitrogen. 917 41

Induction of approximately one dozen genes and/or enzyme activities in liver of the untreated newborn c(14CoS)/c(14CoS) mouse-when compared with the c(ch)/c(14CoS) heterozygote or the c(ch)/c(ch) wild-type-is the result of enhanced levels of reactive oxygenated metabolites originating from a block in the tyrosine degradation pathway. Oxidative stress activates genes via the electrophile response element, whereas dioxin activates genes via the receptor-mediated aromatic hydrocarbon response element. Here, we compared several parameters in 14CoS/14CoS versus ch/ch newborn mouse liver with that in simian virus 40 (SV40)-transformed hepatocyte lines that had been derived from newborn liver. We showed in this study that: (a) NADP(H):quinone oxidoreductase and UDP glucuronosyltransferase 1A6 mRNA levels were increased in both the (untreated) 14CoS/14CoS newborn liver and cell line; (b) aldehyde dehydrogenase 3A1 mRNA was increased by both oxidative stress and dioxin in hepatocyte cultures, but was not detectable in liver of the intact mouse; (c) the glutathione S-transferase GSTA1, GSTP1, GSTA3, and GSTM1 mRNA levels were increased by oxidative stress in 14CoS/14CoS newborn liver, but these transcripts were either low or undetectable in the cell lines; (d) GSTA1 mRNA was up-regulated by the absence of cytochrome P450 1A1 (CYP1A1) activity (i.e. the Gsta1 gene is a member of the aromatic hydrocarbon [Ah] battery); and (e) GSTP1 mRNA was not up-regulated by the absence of CYP1A1 activity (i. e. Gstp1 is not a member of the [Ah] battery). The 14CoS/14CoS and ch/ch hepatocyte established cell lines were transformed with SV40, which expresses large T antigen; this gene product is known to bind to, and interact with, several cell cycle regulatory proteins such as p53 and the retinoblastoma protein-E2F complex. It is therefore likely that differences in the oxidative stress responses between the 14CoS/14CoS newborn liver and the immortalized hepatocyte cell line might be explained by the presence of large T antigen in the established cell line.
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PMID:Comparison of oxidative stress response parameters in newborn mouse liver versus simian virus 40 (SV40)-transformed hepatocyte cell lines. 1067 87