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)

The effect of tetrachloroethylene on Phase I and II drug-metabolizing enzymes in rat liver was examined. Rats were treated orally with tetrachloroethylene daily for five days, at doses of 125, 250, 500, 1,000 and 2,000 mg/kg. The higher doses (> 500 mg/kg) of tetrachloroethylene induced the hepatic microsomal 7-pentoxyresorufin O-depentylase and 7-benzyloxyresorufin O-debenzylase activities associated with the CYP2B subfamily. 7-ethoxyresorufin O-deethylase activity was also induced about 2-fold compared with that of control rats at 500, 1,000, and 2,000 mg/kg dose levels of tetrachloroethylene. However, 7-ethoxycoumarin O-deethylase and 7-methoxyresorufin O-demethylase activities were increased significantly at only the 1,000 mg/kg dose level of tetrachloroethylene (1.4- and 1.5-fold). Although other cytochrome P450-mediated monooxygenase activities such as nitrosodimethylamine N-demethylase, aminopyrine N-demethylase and erythromycin N-demethylase were also induced by tetrachloroethylene, the relative induction to control activity was lower than those of 7-pentoxyresorufin O-depentylase and 7-benzyloxyresorufin O-debenzylase. Western immunoblotting showed that the levels of CYP2B1 and CYP2B2 proteins in liver microsomes were increased at doses of 1,000 and 2,000 mg/kg of tetrachloroethylene. In addition to cytochrome P450-mediated monooxygenases, there was significant induction of the Phase II drug-metabolizing enzymes, DT-diaphorase, glutathione S-transferase activities towards 1-chloro-2,4-dinitrobenzene and 1,2-dichloro-4-nitrobenzene, and UDP-glucuronyltransferase activities towards 4-nitrophenol and 7-hydroxycoumarin. The results indicate that tetrachloroethylene induces both Phase I (CYP2B-mediated monooxygenase) and Phase II drug-metabolizing enzymes (DT-diaphorase, glutathione S-transferase and UDP-glucuronyltransferase) in the rat liver.
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PMID:Induction of rat liver drug-metabolizing enzymes by tetrachloroethylene. 772 43

The induction of hepatic drug-metabolizing enzymes by chlornitrofen (CNP) and CNP-amino was studied in the liver of male rats and mice. CNP-amino increased the activities of 7-pentoxyresorufin O-depentylase (PROD) and 7-benzyloxyresorufin O-debenzylase (BROD) as CYP2B1-dependent monooxygenase 3.6- and 4.1-fold in rats. On the contrary, these enzyme activities in mice were induced by CNP rather than by CNP-amino. Furthermore, immunoblotting showed that the protein levels of CYP2B subfamily cytochrome P450 (P450) in liver microsomes of rats and mice were increased by CNP or CNP-amino. Phase II drug-metabolizing enzymes, UDP-glucuronyltransferase (UGT) and glutathione S-transferase (GST) levels in mice were also significantly increased from 1.4 to 2.5-fold by CNP or CNP-amino. However, neither CNP nor CNP-amino affected UGT and GST in rats. These results suggest that CNP and or CNP-amino induce the P450 isoforms of CYP2B subfamily in the rat and mouse liver, and that the inducibility of drug-metabolizing enzyme by the compounds is different between rats and mice.
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PMID:Induction of hepatic drug-metabolizing enzymes by chlornitrofen (CNP) and CNP-amino in rats and mice. 774 24

The inducing activities of two alkaloids, strychnine and brucine, on the hepatic drug metabolizing enzymes were studied in rats. Administration of strychnine in the drinking water to rats significantly increased the hepatic microsomal activities of benzphetamine N-demethylation, strychnine 2-hydroxylation and testosterone hydroxylations at positions 16 alpha and 16 beta. These results together with that of immunostaining of microsomal proteins revealed that strychnine is a potent inducer of CYP2B1 and 2B2. The comparable induction of CYP2B1/2 was observed by brucine treatment with less toxic effect. Although this inducer increased CYP2B cytochrome P450s (P450s) to the maximum levels after 4 consecutive days of administration, the maximal increase by strychnine was attained after 3 days of administration. Immunoblotting experiment suggested that significant proteolysis of CYP2B1 occurs during treatment by strychnine and brucine. These alkaloids exhibited no ability to induce the activities of testosterone hydroxylations at positions 2 alpha, 6 beta and 7 alpha, benzo[a]pyrene 3-hydroxylation and aniline hydroxylation. In addition to the CYP2B P450, strychnine and brucine induced glutathione S-transferase toward 1-chloro-2,4-dinitrobenzene and UDP-glucuronosyltransferase toward 4-nitrophenol. On the other hand, the glucuronidations of 4-hydroxybiphenyl and morphine were not enhanced by alkaloid treatments. These results indicated that strychnine and brucine cause phenobarbital-like induction of the P450 enzyme, but show a different profile from phenobarbital in the induction of UDP-glucuronosyltransferase.
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PMID:Strychnine and brucine as the potent inducers of drug metabolizing enzymes in rat liver: different profiles from phenobarbital on the induction of cytochrome P450 and UDP-glucuronosyltransferase. 790 30

The effect of genetic obesity and phenobarbital treatment on hepatic conjugation pathways was evaluated in the obese Zucker rat. Acetaminophen pharmacokinetic parameters were examined in vivo after a 30-mg/kg acetaminophen intravenous bolus dose in the presence and absence of phenobarbital treatment. Glucuronidation and glutathione conjugation pathways were studied in vitro in obese and lean Zucker rats after phenobarbital treatment. Obese Zucker rats demonstrated a higher glucuronidation capacity as evidenced by a higher formation clearance of acetaminophen glucuronide and greater UDP-glucuronosyltransferase (UDPGT) activity toward acetaminophen and p-nitrophenol compared with lean controls. Sulfate and glutathione conjugation pathways were not affected by genetic obesity. Obese Zucker rats possessed a higher total hepatic glutathione content due to greater liver weight. Phenobarbital treatment enhanced glucuronidation of acetaminophen and structurally related compounds (i.e., p-nitrophenol) similarly in both phenotypes, but the treatment failed to induce morphine UDPGT in the obese Zucker rat. No effect of phenobarbital was observed on sulfate conjugation, gamma-glutamyl cysteine synthetase activity or hepatic glutathione content in obese or lean Zucker rats. Similar increases in glutathione transferase activities were observed in animals of both phenotypes after phenobarbital treatment. This study demonstrates that glucuronidation is enhanced in genetically obese rats, whereas phenobarbital causes normal induction of several enzymes of the glucuronidation and glutathione conjugation pathways in the obese Zucker rat. However, morphine UDPGT was not induced by phenobarbital, suggesting that obese Zucker rats may possess a defect in the induction of this enzyme similar to that already described for the CYP2B gene in this strain.
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PMID:Effect of genetic obesity and phenobarbital treatment on the hepatic conjugation pathways. 851 12

Induction of isozymes of drug-metabolizing enzymes by butylated hydroxytoluene (BHT) was studied in the male ddY mouse and Chinese hamster. In mice given 0.05 and 0.15% BHT in the diet for 14 days cytochrome P-450 contents and the activities of uridine diphosphate-glucuronyl transferase (UDP-GT) and pentoxyresorufin O-dealkylase were markedly increased, while in those fed 0.15% BHT testosterone 6 alpha-, 16 alpha- and 16 beta-hydroxylases were greatly increased, which indicated induction of cytochrome P-450 isozymes of the CYP2B family. Western blot analysis also showed an increased level of the isozyme immunorelated to rat CYP2B2 by BHT feeding. The activities of aryl hydrocarbon hydroxylase, ethoxycoumarin O-deethylase (ECOD), erythromycin N-demethylase and glutathione S-transferase (GST) remained unchanged. In Chinese hamsters given 0.05 and 0.15% BHT in the diet for 14 days activities of ECOD and GST were induced, but cytochrome P-450 contents and the activities of other enzymes were unaffected. Testosterone 15 alpha-hydroxylase was induced in hamsters fed 0.15% BHT. These findings suggested that BHT administration in the hamster induced CYP2A2-type isozyme, which was confirmed by Western blot analysis. BHT treatment enhanced activation of benzo[a] pyrene (B[a]P) as determined by the mutagenicity test, especially in Chinese hamsters. The results suggest that BHT treatment induces specific isozymes of drug-metabolizing enzymes and might modify the expression of toxicities of other chemicals.
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PMID:Differential induction of isozymes of drug-metabolizing enzymes by butylated hydroxytoluene in mice and Chinese hamsters. 876 52

Rats treated with quinoline, and to a lesser extent, isoquinoline (75 mg/kg, daily for 3 days) showed induction of phase II drug metabolizing enzyme activities without inducing either cytochrome P450 concentration or CYP1A-, CYP2B-, CYP2E-, and CYP3A-selective activities. Elevations of UDP-glucuronosyltransferase activities towards 4-nitrophenol, 1-naphthol, and morphine elicited by quinoline (1.9- to 2.7-fold), were greater than those elicited by isoquinoline (1.4- to 1.8-fold). UDP-glucuronosyltransferase activities towards estrone and testosterone were not increased by either compound. Microsomal epoxide hydrolase activity was increased only by quinoline (2.7-fold). NAD(P)H quinone oxidoreductase activity was increased 2-fold by quinoline and isoquinoline. Cytosolic glutathione S-transferase (GST) activity was increased similarly (approximately 20%) by both agents. Similar treatment of rats with either quinine (75 mg/kg) or chloroquine (150 mg/kg) increased 1-naphthol glucuronidation and GST (quinine only) activities. At 75 mg/kg, chloroquine did not affect any phase II enzyme activities but caused a minor elevation of a phase I enzyme, CYP1A; ascertained from an elevation of 7-ethoxyresorufin deethylase activity and a small hypsochromic shift to the absorbance maximum of the cytochrome P450 CO-complex. With quinoline and isoquinoline treatments (n = 14), the correlation coefficients (R) between microsomal epoxide hydrolase and UDP-glucuronosyltransferase activities towards 4-nitrophenol and morphine were 0.96 and 0.92 respectively, suggesting a highly coordinated induction. The highest NAD(P)H quinone oxidoreductase correlations were with microsomal epoxide hydrolase and UDP-glucuronosyltransferase activities towards 4-nitrophenol and morphine (R approximately 0.78). Correlation coefficients between GST and microsomal epoxide hydrolase and NAD(P)H quinone oxidoreductase activities were approximately 0.49. Quinoline and isoquinoline, nitrogen heterocyclic analogs of naphthalene, join the list of simple nitrogen-containing polycyclic aromatic agents capable of selective induction of phase II drug metabolizing enzymes. The position of the single heterocyclic nitrogen atom in the bicyclic ring influences the magnitude and breadth of the induction response. The addition of bulky ring substituents (quinine, chloroquine) reduced the induction response.
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PMID:Selective induction of phase II drug metabolizing enzyme activities by quinolines and isoquinolines. 913 7

This report describes the establishment and characterization of the mhPKT cell line derived from the liver of a transgenic mouse harboring the simian virus (SV40) large T and small t antigens placed under the control of the 5' regulatory sequence of the rat L-type pyruvate kinase (L-PK) gene. mhPKT cells had a prolonged life span, expressed the SV40-encoded nuclear large T antigen when grown in glucose-enriched medium, and induced tumors when injected subcutaneously into athymic (nu-nu) mice. Growth on petri dishes or filters yielded multiple layers of cuboid cells, with numerous spaces between adjacent cells that were closed by junctional complexes. These bile canaliculi-like structures exhibited numerous microvilli in which villin, an actin-binding brush-border protein, colocalized with actin. These bile canaliculi-like structures appeared to be functional as they accumulated fluorescein. mhPKT cells conserved the expression of the liver-specific transcription factors HNF1, HNF3, HNF4, and DBP together with substantial levels of L-PK and albumin but not alpha-fetoprotein mRNA transcripts. mhPKT cells mainly metabolized testosterone into androstenedione and 6beta-hydroxytestosterone, as in vivo. 3-Methylcholanthrene and 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) markedly increased ethoxyresorufin-O-deethylase activity and the related cytochrome P450 (CYP) 1A1/2 protein, whereas alpha-naphtoflavone antagonized the TCDD-elicited induction. Phenobarbital slightly increased the CYP2B-mediated activities of pentoxyresorufin-O-depentylase, 2beta- and 16beta-testosterone hydroxylase. mhPKT cells also had substantial sulfotransferase, UDP-glucuronyltransferase, and glutathione S-transferase activities. This model may serve as a tool for long-term in vitro studies of xenobiotic metabolism, potent CYP inducers, and hepatocyte damage due to drugs and other factors.
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PMID:Activity and inducibility of drug-metabolizing enzymes in immortalized hepatocyte-like cells (mhPKT) derived from a L-PK/Tag1 transgenic mouse. 926 Sep 6

Induction mode of the hepatic drug-metabolizing enzymes was studied in Corn snake (Elaphe guttata emoryi). Treatment of snakes with 3-methylcholanthrene or phenobarbital produced no effects on liver weight and total content of cytochromes P450 and b5. Treatment with 3-methylcholanthrene significantly induced the activities of arylhydrocarbon hydroxylase, 7-ethoxyresorufin O-deethylase and 7-pentoxyresorufin O-dealkylase, whereas those of ethoxycoumarin O-deethylase, benzphetamine N-demethylase, erythromycin N-demethylase and testosterone hydroxylases were not affected. 3-Methylcholanthrene-induced activities of 7-ethoxyresorufin O-deethylase and 7-pentoxyresorufin O-dealkylase were inhibited by 20 microM alpha-naphthoflavone by 98% and 73%, respectively. Phenobarbital-treatment caused a significant induction of the activities of erythromycin N-demethylase and testosterone 6 beta-hydroxylase, but did not affect those of the other phase I enzymes and the other testosterone hydroxylases. The activities of UDP-glucuronyltransferase and glutathione S-transferase were not affected by either 3-methylcholanthrene or phenobarbital administration. Immunoblotting showed that 3-methylcholanthrene-treatment induced a protein band related to hamster CYP1A2, and decreased the intensity of the two bands detected with anti-rat CYP2B1. Phenobarbital-treatment did not affect the intensity of CYP2B-related proteins. The results suggest that snake liver has multiple forms of cytochrome P450, notably those inducible by 3-methylcholanthrene.
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PMID:Modulation of snake hepatic cytochrome P450 by 3-methylcholanthrene and phenobarbital. 966 83

The objective of the present study was to investigate the expression of major xenobiotic-metabolising cytochrome P450 proteins, and of other enzyme systems, in hepatic and extrahepatic tissues of rabbits rendered atherosclerotic by the dietary administration of 1% cholesterol diets for 8 weeks. Individual cytochrome P450 proteins were monitored using diagnostic substrates and immunologically in Western blot analysis. The activity of all hepatic isoforms studied was depressed in the atherosclerotic animals; when, however, apoprotein levels were determined immunologically, no major differences were evident between the control and the atherosclerotic rabbits. In vitro studies indicated that neither cholesterol nor palm oil inhibited cytochrome P450 activity. The effects of cholesterol treatment leading to atherosclerosis on kidney, heart and lung cytochrome P450 activities were isoform- and tissue-specific; no change was evident in the heart activities, but in the lung and kidney cytochrome P450 activities were clearly modulated by the treatment with cholesterol. Apoprotein levels did not always parallel the changes in activities. Western blot analysis of aortic cytochromes P450 revealed that administration of cholesterol-rich diets enhanced CYP2B and CYP3A apoprotein levels. Cholesterol feeding to rabbits gave rise to a marked decrease in hepatic glutathione S-transferase activity but did not influence glutathione reductase or total glutathione levels. The same treatment had no effect on catalase, glutathione peroxidase and superoxide dismutase. It is concluded that treatment of rabbits with cholesterol-rich diets leading to atherosclerosis gives rise to profound changes in the expression of cytochrome P450 proteins in the liver and other tissues; possible mechanisms are discussed.
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PMID:Marked inhibition of hepatic cytochrome P450 activity in cholesterol-induced atherosclerosis in rabbits. 967 66

4-Vinylcyclohexene (VCH), an ovarian toxicant in mice, is known to irreversibly deplete ovarian follicles as a consequence of VCH diepoxide formation. Because ovotoxicity requires repeated dosing of VCH, the effect of consecutive daily doses of VCH (7.5 mmol/kg/day) on mouse liver microsomal activities and VCH epoxidation was determined. Cytochromes P-450 2B and 2A (CYP2B and CYP2A), principle isoforms involved in the bioactivation of VCH, as well as CYP2E1 and CYP3A were evaluated. VCH exposure increased total cytochrome P-450 content (35-83% above control levels) after either 5, 10, or 15 days of treatment. Western blot analysis revealed an induction of CYP2A, CYP2B, and CYP2E1 at day 10. Elevated levels of CYP2A and CYP2B correlated with marker androstenedione and testosterone 16alpha- and 16beta-hydroxylase activities. Microsomes prepared from mice pretreated with VCH for 10 days demonstrated an increase (>/=2-fold) in the rate of VCH monoepoxide and diepoxide formation. Microsomal VCH epoxidation was increased to a similar extent by phenobarbital, acetone, and dexamethasone treatment. An increase in cytosolic glutathione S-transferase activity was observed after repeated VCH treatment, an enzyme potentially involved in detoxification of the VCH epoxides. Interestingly, preliminary studies indicated that circulating levels of the monoepoxide (vinylcyclohexene 1, 2-monoepoxide) and diepoxide of VCH were elevated after repeated dosing of VCH. Overall, the results indicate that repeated exposure of VCH in mice induces cytochrome P-450-dependent activities, and in turn induction of its metabolism. Additional studies examining the toxicokinetics of VCH after repeated exposure are required to further delineate the relevance of induction in VCH-induced ovotoxicity.
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PMID:Induction of cytochrome P-450 enzymes after repeated exposure to 4-vinylcyclohexene in B6C3F1 mice. 992 17


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