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)

Little is known about the effects of aging on the hepatic drug metabolizing capacity of horses despite the relatively long lifespan characterizing this species. A wide array of cytochrome P450 (CYP)-dependent monooxygenases, carboxylesterases and transferases were assayed in liver microsomes from 50 female horses in an age range between less than 1 year to over 12 years. Rather unexpectedly, both the CYP content and the activity of NADPH cytochrome c reductase rose as a function of age. Accordingly, a general increasing trend was recorded in the rate of the in vitro metabolism of the substrates reported to be related to CYP2B-, CYP2E- or CYP3A, although, as detected by Western immunoblotting, only the levels of proteins recognized by anti-rat CYP3A- and CYP2B antibodies appeared to increase consistently. Also the carboxylesterases and uridindiphosphoglucuronyl-transferase (UGT) activity toward 1-naphthol displayed a similar trend, glutathione S-transferase accepting 3,4-dichloronitrobenzene as a substrate being the only enzyme activity showing an age-related decline. A positive correlation was also found between liver cadmium content and CYP amount as well as the activities of most monooxygenases (except for those related to CYP1A), carboxylesterases, and UGT. While confirming that a number of enzyme activities are less expressed in foals, our results contradict the general view that the drug metabolizing capacity drops in elder individuals. Although several other factors can influence the kinetics of foreign compounds in aged animals, data from this study may provide insight in understanding possible age-related differences in drug efficacy and the response to toxic substances in horses.
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PMID:Postnatal development of hepatic oxidative, hydrolytic and conjugative drug-metabolizing enzymes in female horses. 1473 5

The induction of CYP2B gene expression by phenobarbital (PB) is mediated by the translocation of the constitutive androstane receptor (CAR) from the cytoplasm to the nucleus. The CAR/RXR heterodimer binds to two DR-4 sites in a complex phenobarbital responsive unit (PBRU) in the CYP2B gene. The short heterodimer partner (SHP), an orphan nuclear receptor that lacks a conventional DNA binding domain, was initially identified by its interaction with CAR. We have examined the role of SHP in CAR-mediated transactivation of the CYP2B gene. Coexpression of SHP inhibited the transactivation of the CYP2B gene by CAR in cultured hepatoma cells and the p160 coactivator GRIP1 reversed the inhibition. The interaction of CAR with SHP was confirmed by GST pulldown experiments. SHP did not block the binding of either CAR/RXR to the PBRU or binding of GRIP1 to the CAR/RXR complex in gel mobility shift assays, but slightly increased CAR/RXR binding and slightly altered the mobility of the CAR/RXR/GRIP1 complex, suggesting an interaction of SHP with these complexes. The presence of SHP in the complexes, however, could not be detected in an antibody supershift assay. Recombinant corepressors mSin3A, SMRT, and HDAC1, but not NCoR1, interacted with GST-SHP but each of these corepressors in liver nuclear extracts bound to GST-SHP. SMRT and NCoR1 inhibited CAR-mediated activation independent of SHP, but mSin3A and HDAC1 had little effect alone, and were additive with SHP. These studies demonstrate that SHP does not inhibit CAR-mediated trans-activation by interfering with DNA binding or by competition with GRIP1. Instead, SHP may either inhibit recruitment of other coactivators by GRIP1 or actively recruit corepressors directly to the CAR/RXR/PBRU complex.
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PMID:Repression of CAR-mediated transactivation of CYP2B genes by the orphan nuclear receptor, short heterodimer partner (SHP). 1500 Jul 48

Naturally occurring phenolics, protocatechuic and tannic acids have been reported to be inhibitors of chemical mutagenesis and carcinogenesis in experimental models. Here, we have studied the effect of pretreatment with these compounds on MC-induced cytochrome P450 and phase II enzymes in rats. The male Wistar rats were treated intraperitoneally with protocatechuic acid and tannic acid in the dose of 50mg/kg every 3 days for 2 weeks. MC was administered at the 12th day of phenolics treatment. The activities of EROD (CYP1A1), MROD (CYP1A2), PROD (CYP2B), PNPH (CYP2E1), GST, UDPGT, NQO1 were measured in the liver and kidney. Protocatechuic acid treatment minimally reduced the MC-induced EROD and MROD, but the observed differences were statistically significant. This compound was also a weak inhibitor of hepatic PNPH. Moreover, Western blot analysis with CYP1A1/1A2- and CYP2E1-specific antibodies showed the same effect in the levels of hepatic CYP1A1/1A2 and CYP2E1. Minimal decrease of renal constitutive (by 23%) and more significant reduction of induced form (by 66%) of PNPH was found as result of treatment with protocatechuic acid. Tannic acid alone had no effect on cytochrome P450 enzymes while in combination with MC this polyphenol minimally enhanced the MC induction of MROD and in greater extent PNPH in liver. The treatment with protocatechuic acid alone enhanced slightly the activities of all three phase II enzymes in liver. The pretreatment with this phenolic of the MC-induced rats however significantly increased the activities of hepatic GST and NQO1 in comparison with MC-treated group. In kidney MC-induced activity of NQO1 was reduced (about 43%) to the control level by tannic acid pretreatment. The results of our present study indicate that in rat the prolonged treatment with protocatechuic acid affects differently the activities of CYP and phase II enzyme when compared to tannic acid. Moreover, the effect of this polyphenols significantly depends on the method of treatment.
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PMID:Modulation of 3-methylcholanthrene-induced rat hepatic and renal cytochrome P450 and phase II enzymes by plant phenols: protocatechuic and tannic acids. 1530 93

The effect of food restriction on the specific activities of the drug metabolizing enzymes (DME) system was studied in Holtzman male rats by comparing DME activities in 90-day-old control rats fed ad libitum (CO), rats fed 40% restricted food (RF) from the gestation period to the day of sacrifice, and recovered rats (rRF) fed 40% restricted food from period of gestation to 45 days of age and then fed ad libitum until the day of sacrifice. In liver, total cytochrome P450 (CYP) of the RF and rRF groups was higher by approximately 50% and 28%, respectively, than in CO rats. Specific activities of individual CYP monooxygenases (MO) such as CYP2B [7-methoxycoumarin demethylase (MOCD)], CYP1A [aryl hydrocarbon hydroxylase (AHH) and ethoxyresorufin deethylase (EORD)], and CYP2E [nitrosodimethylamine demethylase (NDMAd)] were 31, 61, 43, and 56% in RF and 16, 36, 26, and 32% in rRF groups, respectively, more than the CO values. Conjugases such as UDP- glucuronosyltransferases with substrates 3-OH benzo(a)pyrene (UGT1) and 4-hydroxybiphenyl (UGT2) and glutathione S-transferase (GST) with substrate 1-chloro-2,4-dinitrobenzene were higher by 72, 69, and 33% in RF and 28, 38, and 24% in rRF groups, respectively. MO activities (MOCD and EORD) were significantly higher in lung, kidney, and intestine: MOCD by 82, 48, and 45% in RF and 40, 25, and 22% in rRF, respectively; and EORD by 84, 77, and 67% in RF and 40, 33, and 28% in rRF, respectively. However, activity of conjugases (UGT1 and GST) were significantly lower (approximately 35-45%) in RF and rRF rats (approximately 20-30%) than in the CO group in above mentioned extrahepatic tissues. These studies indicate that undernourishment during the period of gestation, weanling, and growth and development of microsomal enzymes produces a sequela of events on the DME in hepatic and extrahepatic tissues that cannot return to the control values even when fed ad libitum.
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PMID:Malnutrition sequela on the drug metabolizing enzymes in male Holtzman rats. 1553 57

The principal objectives of our study were to ascertain whether sulforaphane, at dietary levels of intake, modulates rat hepatic cytochrome P450 and phase II enzyme systems and to evaluate the impact of such changes in the chemopreventive activity of this isothiocyanate. Animals were exposed to sulforaphane in their drinking water for 10 days, equivalent to daily doses of 3 and 12 mg/kg. Depentylation of pentoxyresorufin decreased and was paralleled by a decline in CYP2B apoprotein levels. At the higher dose, erythromycin N-demethylase activity declined and was accompanied by a similar decrease in CYP3A2 apoprotein levels. However, sulforaphane treatment upregulated CYP1A2 levels, determined immunologically, but the dealkylations of methoxy- and ethoxyresorufin were not similarly increased. Hepatic S9 preparations from sulforaphane-treated rats were less effective than control preparations in converting IQ (2-amino-3-methylimidazo-[4,5-f]quinoline) to mutagenic intermediates in the Ames test. To clarify the underlying mechanism, in vitro studies were undertaken. In beta-naphthoflavone-treated rats, the inhibition by sulforaphane of the O-dealkylations of methoxy- and ethoxyresorufin was enhanced if the isothiocyanate was preincubated in the presence of NADPH. It may be inferred that sulforaphane induces hepatic CYP1A2 but the enzyme is not catalytically competent because of bound sulforaphane metabolite(s). Finally, sulforaphane stimulated, in a dose-dependent fashion, quinone reductase but failed to influence glutathione S-transferase, epoxide hydrolase and glucuronosyl transferase activities. It is concluded that, even at dietary doses, sulforaphane can modulate the xenobiotic-metabolising enzyme systems, shifting the balance of carcinogen metabolism toward deactivation, and this may be an important mechanism of its chemopreventive activity.
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PMID:Modulation of hepatic cytochromes P450 and phase II enzymes by dietary doses of sulforaphane in rats: Implications for its chemopreventive activity. 1590 51

The liver is the main organ of drug metabolism, but the expression and induction by xenobiotics of drug-metabolizing enzymes is also often observed in extrahepatic tissues. Recently, we reported that lipophilic cytochrome P450 inducers, beta-naphthoflavone (BNF), phenobarbital, and dexamethasone, induced CYP1, CYP2B, and CYP3A enzymes, respectively, in rat epididymal white adipose tissue (WAT) at both mRNA and protein levels. To further confirm the xenobiotic-induced expression of drug-metabolizing enzymes in adipose tissue, we studied the induction of CYP1A1 and other detoxifying enzymes by aryl hydrocarbon receptor (AhR) agonists and antioxidants. BNF increased CYP1A1 mRNA levels in several visceral WATs (epididymal, perirenal, and mesenteric) to a greater degree than in subcutaneous WAT in rats. Using C57BL/6 and DBA/2 mice with different responsiveness to aryl hydrocarbons and detecting cytoplasmic levels of AhR proteins, we have demonstrated that AhR mediates this CYP1A1 induction by BNF in WAT. Moreover, the NF-E2-related factor 2 (Nrf2)/antioxidant responsive element pathway is also functional in WAT, since BNF, which is known to activate both AhR and Nrf2, and antioxidants including tert-butylhydroquinone, 1-chloro-2,4-dinitrobenzene, and menadione induced the expression of Nrf2-target genes (NAD-(P)H:quinone oxidoreductase, glutathione S-transferase A subunits, and heme oxygenase-1) in rats and mice. These results suggest that both AhR and Nrf2 pathways are active in WAT and that lipophilic compounds accumulated in WAT can activate these transcription factors to increase detoxification capability in the tissue.
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PMID:Induction of detoxifying enzymes in rodent white adipose tissue by aryl hydrocarbon receptor agonists and antioxidants. 1658 46

The effects of fungicide bitertanol on cytochrome P450-dependent monooxygenases were studied using rats treated intraperitoneally with the N-substituted triazole for 4 days. Treatment with 10, 25, and 100 mg/kg bitertanol produced 2-, 4-, and 14-fold increases of 7-ethoxyresorufin O-deethylation activity in liver microsomes, respectively. Immunoblot analysis of microsomal proteins revealed that 25 mg/kg bitertanol increased CYP1A1 protein in the liver, kidney, and lung by 10-, 13-, and 17-fold, respectively. Bitertanol produced smaller increases of CYP2B and CYP3A catalytic activity and protein than that of CYP1A1 in liver. RT-PCR analysis of total RNA indicated that bitertanol-induced CYP1A1, CYP2B, and CYP3A mRNA. Additions of 0.01-100 microM bitertanol to liver microsomes from rats treated with 25 mg/kg bitertanol or 3-methylcholanthrene inhibited microsomal 7-ethoxyresorufin O-deethylation activity (IC(50)=0.8 or 0.9 microM). Bitertanol at 100 mg/kg increased liver UDP-glucuronosyltransferase and glutathione S-transferase activities by 2-fold. Bitertanol at 25 mg/kg produced a minor increase in metabolic activation of benzo[a]pyrene by liver S-9 fraction in the Ames mutagenicity test while the increase was blocked by addition of 100 microM bitertanol. These findings show that bitertanol is an inducer of CYP1A1, CYP2B, and CYP3A in vivo and an inhibitor of CYP1A catalytic activity in vitro.
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PMID:Induction and inhibition of cytochrome P450-dependent monooxygenases of rats by fungicide bitertanol. 1697 Oct 34

The challenge of consuming plant compounds that are recognized to have toxic physiological effects is an unavoidable consequence of an herbivorous diet and requires mechanisms to metabolize and eliminate them after consumption. We took a pharmacological approach to understanding how an oak (Quercus agrifolia) specialist (Neotoma macrotis) and generalist (N. lepida) herbivores process the same dietary toxins. Oak contains polyphenolic compounds considered toxic to most other mammals. N. macrotis includes up to 85% of oak in their diet. N. lepida includes oak as a portion of the diet but is considered a generalist in areas where sympatric with N. macrotis. Xenobiotic metabolizing enzyme activities of N. macrotis and N. lepida were investigated after animals were fed a 70% oak diet and a toxin-free control diet. Biotransformation activities of five major enzymes [cytochrome P450s (CYP), NAD(P)H/quinone oxidoreductase (QOR), UDP-glucuronosyltransferase (UGT), sulfotransferase (SULT), and glutathione S-transferase (GST)] and three specific CYP isozymes (CYP1A, CYP2B, and CYP3A) were investigated. The results indicate that, with the exception of CYP2B induction, N. macrotis and N. lepida enzyme activities are not changed by an oak diet. The major differences in enzyme activities were constitutive. The specialist, N. macrotis, had higher constitutive activity of QOR, UGT, and GST. The generalist, N. lepida, had higher constitutive activity levels of CYP1A and SULT.
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PMID:Xenobiotic metabolism of plant secondary compounds in oak (Quercus agrifolia) by specialist and generalist woodrat herbivores, genus Neotoma. 1792 91

Cattle represent an important source of animal-derived food-products; nonetheless, our knowledge about the expression of drug-metabolizing enzymes (DMEs) in present and other food-producing animals still remains superficial, despite the obvious toxicological consequences. Breed represents an internal factor that modulates DME expression and catalytic activity. In the present work, the effect of breed upon relevant phase I and phase II DMEs was investigated at the pretranscriptional and post-translational levels in male Charolais (CH), Piedmontese (PM) and Blonde d'Aquitaine (BA) cattle. Because specific substrates for cattle have not yet been identified, the breed effect upon specific cytochrome P450 (P450), UDP-glucuronosyltransferase (UGT), or glutathione S-transferase (GST) DMEs, in terms of catalytic activity, was determined by using human marker substrates. Among P450s, benzphetamine N-demethylase, 16beta-, 6beta-, and 2beta-testosterone hydroxylase, aniline and p-nitrophenol hydroxylase, and alpha-naphthol and p-nitrophenol UGT activities were significantly higher in CH; in contrast, lower levels of CYP1A1-, CYP1A2-, CYP2B6-, CYP2C9-, CYP2C18-, CYP3A4-, and UGT1A1-like mRNAs were noticed, with CH < PM < or = BA as a trend. CYP2B and CYP3A mRNA results were confirmed with immunoblotting, too. As regards conjugative DMEs, UGT1A6-like mRNA levels were consistent with respective catalytic activities. Both 1-chloro-2,4-dinitrobenzene and 3,4-dichloronitrobenzene GST activities were higher in BA, and these results agreed with GSTA1-, GSTM1-, and GSTP1-like mRNA amounts. Correlation analysis between catalytic activities and mRNAs showed either significant or uneven results, depending on the substrate. These findings confirm previous data obtained in laboratory species; however, further studies are required to ascribe this behavior to pretranscriptional or post-translational phenomena.
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PMID:Effect of breed upon cytochromes P450 and phase II enzyme expression in cattle liver. 1826 77

The aim of the present study was to investigate the interaction of 2,4,6-trinitrotoluene (TNT) with liver biotransformation enzymes in European eel Anguilla anguilla (Linnaeus, 1758). Eels were exposed to 0.5, 1 and 2.5mg/l nominal concentrations of TNT for 6 and 24h. Modulation of CYP1A1, UDPGT and GST genes was investigated by real-time PCR. Total CYP450 content, NADPH cytochrome c reductase activity, CYP1A and CYP2B-like activities, such as EROD, MROD and BROD, as well as GST and UDPGT activities, were measured by biochemical assays. An in vitro study was performed on EROD in order to evaluate catalytic modulation by TNT. No modulation of the CYP1A1 gene or protein was observed in TNT-exposed eels. On the other hand, a significant decline of EROD and MROD activities was observed in vivo. An increase in NADPH cyt c reductase, and phase II enzymes (UDPGT and GST) were observed at both gene expression and activity levels. The overall results indicated that TNT is a potential competitive inhibitor of CYP1A activities. A TNT metabolic pathway involving NADPH cyt c reductase and phase II enzymes is also suggested.
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PMID:Interactions of 2,4,6-trinitrotoluene (TNT) with xenobiotic biotransformation system in European eel Anguilla anguilla (Linnaeus, 1758). 1840 54


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