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)

The emergence of drug resistance is a major obstacle to effective cancer chemotherapy. The identification of novel agents that serve as selective, potent and nontoxic modulators of drug resistance is thus an important goal for improving the success of cancer treatment. Thaliblastine (TBL), a plant alkaloid and P-glycoprotein (P-gp) inhibitor, is presently shown to fully reverse 490-fold resistance to Adriamycin (AdR) in a multidrug-resistant (MDR) human breast cancer cell line (MCF/AdR) that overexpresses P-gp, whereas the same treatment had no effect on AdR cytotoxicity in the drug-sensitive parental MCF-7 cells. Mechanistic studies showed that this striking resistance reversal was achieved without alteration of cellular levels of glutathione and without inhibition of glutathione S-transferase, glutathione peroxidase or P450 reductase by TBL, each of which is significantly altered in MCF/AdR cells, and each of which has been proposed to contribute to AdR resistance in this MDR line. Rather, resistance reversal by TBL can be entirely explained by this drug's capacity to restore the intracellular accumulation of AdR in the resistant cells. These results establish that MDR associated with P-gp overexpression can be fully reversed by the potent P-gp inhibitor TBL. They further indicate that although changes in multiple drug-metabolizing enzymes may accompany the development of MDR, these multiple biochemical alterations need not correspond to multiple functional determinants for drug resistance.
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PMID:Complete reversal by thaliblastine of 490-fold adriamycin resistance in multidrug-resistant (MDR) human breast cancer cells. Evidence that multiple biochemical changes in MDR cells need not correspond to multiple functional determinants for drug resistance. 756 98

The Cyp 2d-9 gene encodes the male-specific steroid 16 alpha-hydroxylase in mouse liver and shares a conserved regulatory element (-100TTCCGGGC-93) with another male-specific Slp promoter. As shown with the Slp promoter (N. Yokomori, R. Moore, and M. Negishi, Proc. Natl. Acad. Sci. USA 92:1302-1306, 1995), the male-preferential demethylation also occurs at CpG/-97 in the Cyp 2d-9 promoter. The transcription factor which specifically binds to the demethylated element has been purified. The peptide sequences reveal that the factor consists of GABP alpha and GABP beta 1 with Ets and Notch motifs, respectively. Both DNase I footprinting and gel shift assays indicate that the bacterially expressed glutathione S-transferase-GABP fusion proteins bind to the regulatory element only when CpG/-97 is demethylated. Moreover, Cyp 2d-9 promoter is trans-activated by coexpression of GABP proteins in HepG2 cells. Given the additional results that CpG/-50 of the female-specific steroid 15 alpha-hydroxylase (Cyp 2a-4) promoter is preferentially demethylated in the females, the sex-specific expressions of the P450 genes correlate very well with DNA demethylation. We also conclude that GABP is a methylation-sensitive transcription factor and is a potential transcription activator of the male-specific Cyp 2d-9 promoter.
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PMID:A DNA methylation site in the male-specific P450 (Cyp 2d-9) promoter and binding of the heteromeric transcription factor GABP. 756 85

Hepatocarcinogenic aromatic amines such as 4-aminoazobenzene derivatives and heterocyclic aromatic amines of cooked food origin were found to be liver-selective cytochrome P450IAZ (CYP1A2) inducers. Each aromatic amine showed different species-specificity among rodent experimental animals in terms of the extent of P450 induction. Carcinogenic susceptibility of an animal to the amine was well correlated with the activity and/or inducibility of CYP1A2 in the animals in the early initiation phase of the carcinogenesis. In hyperplastic nodules of rat liver, expression and induction of CYP1A2 as suppressed, especially in the placental form of glutathione S-transferase-positive foci. Despite the decrease of P450s including CYP1A2 in the rat liver bearing hyperplastic nodules. DNA adducts formed by a carcinogenic aromatic amine increased, as compared to the controls, suggesting that the activity of DNA repair enzyme(s) for the amine-derived DNA adducts might decrease in the hyperplastic nodules of rat liver. Treatment of rats with lead nitrate revealed a pattern of P450 expression in the liver similar to that observed with rats bearing hyperplastic nodules. These findings may provide valuable information on the roles of P450s in carcinogenic susceptibility of animals to aromatic amines and in the carcinogenic process.
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PMID:Induction of cytochrome P450 isoforms by carcinogenic aromatic amines and carcinogenic susceptibility of rodent animals. 758 95

1. The metabolism of a nitrate ester-substituted dihydropyridine derivative (NND) in vitro was characterized with rabbit hepatic microsomes and cytosol. 2. Denitration activity was located in both the microsomal and cytosolic fractions, whereas oxidation to the pyridine analogue was solely located in the microsomal fraction. 3. Oxidation to the pyridine analogue required NADPH and was inhibited by carbon monoxide, miconazole and SKF-525A, suggesting that oxidation was catalysed by P450. 4. Denitration activity in the microsomes required either NADPH or GSH. Together with these results, responses to various inhibitors indicate participation of both P450 and glutathione S-transferase (GST). 5. Denitration activity in cytosol was activated by glutathione (GSH), and by dithiothreitol (DTT) to a greater extent. GSH-dependent denitration was inhibited by S-hexyl GSH, an inhibitor of GST, but DTT-dependent denitration was not. Moreover, the formation patterns of the mono-denitrated metabolites, M1 and M2, were shown to be different in each incubation condition. 6. These results suggest that the denitration of NND in cytosol could be catalysed by a GSH-independent enzyme as well as the GSH-dependent enzyme, GST.
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PMID:Metabolism of a nitrate ester, dihydropyridine derivative in rabbit hepatic microsomes and cytosol. 761 54

It has been shown previously that the anticonvulsant agent, sodium valproate, induces certain cytochrome P-450 monooxygenase activities and decreases glutathione S-transferase activity. We have used Western blotting, RNase protection assays and Northern blot hybridization to determine the effects of valproate on the abundance of individual components of the cytochrome P-450 monooxygenase and of glutathione S-transferase subunits. Due to the short half-life of the drug in rats we have used an in vitro experimental system comprised of rat hepatocytes co-cultured with rat primitive biliary epithelial cells. Valproate was shown to be a potent inducer of two members of the cytochrome P-450 (CYP)2B subfamily, CYP2B1 and 2B2. The induction of the proteins was mediated at the level of the mRNAs, with the mRNA for CYP2B1 being more highly induced than that for CYP2B2. The drug also induced, but to a much lesser extent, two important components of the cytochrome-P-450-mediated monooxygenase system, NADPH-dependent cytochrome P-450 reductase and cytochrome b5, and their corresponding mRNAs. Thus, the effects of valproate on cytochromes P-450 and other components of the cytochrome-P450-mediated monooxygenase system mimic those of another, structurally diverse, antiepileptic drug, phenobarbital. However, in contrast to phenobarbital, which induces glutathione S-transferase subunits 1, 2, 3, 4 and 7, valproate selectively decreases the abundance of subunits 3 and/or 4. It has been shown previously that CYP2B1 is involved in the production of metabolites of valproate implicated in hepatotoxicity. The induction of this protein by valproate would thus contribute substantially to the hepatotoxic effects associated with the drug.
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PMID:Effects of the anticonvulsant, valproate, on the expression of components of the cytochrome-P-450-mediated monooxygenase system and glutathione S-transferases. 763 45

By use of an isolation procedure including centrifugal elutriation and density gradient centrifugation, relatively pure fractions of Clara cells and type II cells were obtained from rabbit lungs. These cells and alveolar macrophages isolated by lavage were exposed to methyl methanesulfonate (MMS), 1,2-dibromo-3-chloropropane (DBCP), 1-nitropyrene (1-NP), 2-nitrofluorene (2-NF), 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK), N'-nitrosonornicotine (NNN), N-nitrosoheptamethyleneimine (NHMI) or phorbol 12-myristate 13-acetate (TPA). DNA damage measured as alkali-labile sites and/or single-strand breaks was then determined in the different lung cells by an automated alkaline elution system. The direct-acting compound MMS showed similar DNA-damaging effect in Clara cells, type II cells and alveolar macrophages. The nematocide DBCP, activated by both P450- and glutathione S-transferase(s)-dependent pathways, caused considerably less DNA damage in macrophages than in Clara or type II cells. Similar differences between the lung cells in induction of DNA damage as observed with DBCP were demonstrated after exposure to the activation-dependent nitrosamines NNK and NHMI and the tumor promoter TPA. The other test substances (1-NP, 2-NF, NNN) did not cause any marked DNA damage measured by the alkaline elution technique. These findings are in agreement with the known metabolic capacity of these cell types, indicating that Clara and type II cells are possible primary targets for lung toxic/carcinogenic compounds.
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PMID:Chemically induced DNA damage in isolated rabbit lung cells. 767 4

We previously reported that LEC rats, which show a spontaneous occurrence of liver injury and hepatocellular carcinoma (HCC), are highly susceptible to chemical carcinogens such as diethylnitrosamine (DEN). Since abnormal copper accumulation in the liver of LEC rats was found to be a cause of liver injury, it is necessary to elucidate whether the carcinogen susceptibility of LEC rats is related to the accumulation of copper in the liver. In this study we have examined the relationship between the susceptibility of FI [LEC x LEA or LEC x Fischer 344 (F344)] and FI backcross rats to DEN and hepatic copper concentration, as copper accumulation has been demonstrated to be inherited as an autosomal recessive trait. The groups of F1 and F1 backcross rats were given a single intraperitoneal injection of DEN (20 mg/kg wt) and subjected to a modified Solt-Farber protocol for assaying glutathione S-transferase placental form (GST-P)-positive foci. The hepatic copper concentration was examined by atomic absorption. Although no F1 rats showed a high copper concentration in the liver, the numbers of foci were as high as those in LEC rats which accumulate copper. Backcross rats separated into high and low copper concentration groups at an almost 1:1 ratio, but there was no significant difference in the mean numbers of foci between these two groups. The results clearly indicate that the high susceptibility of LEC rats to DEN is genetically independent of copper accumulation in the liver. A possible dominant inheritance of this high carcinogen susceptibility was suggested. Biochemical measurement of cytochromes P450 and b5 in the liver of F1 rats indicated that alterations in drug metabolizing enzymes may be partially responsible for the high carcinogen susceptibility of LEC rats.
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PMID:The high hepatocarcinogen susceptibility of LEC rats is genetically independent of abnormal copper accumulation in the liver. 769 3

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

Our previous studies (Sidhu JS et al. Arch Biochem Biophys 1993: 301, 103-113; Sidhu JS et al. In Vitro Toxicol 1994: 7, 225-242) demonstrated the importance of culturing primary rat hepatocytes with an overlay of extracellular matrix (ECM), together with optimal media formulations (Williams' E or Chee's), to efficiently maintain in vivo-like responsiveness of phenobarbital (PB)-inducible cytochrome P450 genes in vitro. In the present report, we have characterized culture conditions further by examining individual and interactive effects of dexamethasone (Dex) and PB on CYP2B1, CYP2B2, and CYP3A1 expression. Dex alone was not effective in enhancing CYP2B1 or CYP2B2 expression levels. However, together with PB, addition of low concentrations (10(-9)-10(-8) M) of Dex resulted in a marked potentiation of PB-inducible P450 gene expression. In contrast, at levels > 10(-7) M, Dex profoundly inhibited PB induction of the CYP2B1 and CYP2B2 genes. The overall stimulatory response to Dex was more dramatic in cells cultured in Williams' E than in Chee's medium. Similarly, concentrations of PB > 0.5 mM resulted in substantially reduced levels of CYP2B1 and CYP2B2 induction than those attainable at lower PB concentrations. These results suggest that Dex and PB function cooperatively to regulate the CYP2B1 and CYP2B2 genes, and that composite interactions may either negatively or positively regulate expression, in a concentration-dependent manner. CYP3A1 was not regulated in a similar biphasic fashion, as this gene was fully responsive even at high dose levels of PB or Dex. With respect to other marker genes evaluated, high Dex concentrations (> 10(-7) M) were only marginally inhibitory to beta-naphthoflavone-mediated induction of CYP1A1 and CYP1A2 mRNAs, and did not perturb expression of the liver-selective serum albumin gene. Addition of Dex was critical, however, to maintain glutathione S-transferase Pi expression, a marker of hepatocyte dedifferentiation, in the repressed state. Defining optimal culture conditions for maintaining hepatocyte differentiation in vitro are requisite for establishing primary culture models enabling investigation of the molecular mechanisms of PB-mediated gene regulation.
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PMID:Modulation of xenobiotic-inducible cytochrome P450 gene expression by dexamethasone in primary rat hepatocytes. 777

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


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