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)

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.
 ...
PMID:Drug-metabolizing enzyme activities in freshly isolated oval cells and in an established oval cell line from carcinogen-fed rats. 807 23

Several classes of compounds are able to induce a spectrum of drug-metabolizing enzymes without inducing cytochrome P450s. Examples include antioxidants such as tert-butyl-4-hydroxyanisole and its metabolite tert-butylhydroquinone, dithiolthiones such as oltipraz, and N-heterocycles such as 1,7-phenanthroline. The events associated with induction of UDP-glucuronosyltransferases (UGT), glutathione S-transferases, and microsomal epoxide hydrolase after a single oral dose of these agents have been compared. No agent significantly elevated any of these enzyme activities within 24 h, but oltipraz and 1,7-phenanthroline significantly increased glutathione S-transferase and UGT activities by 48 h. 1, 7-Phenanthroline and oltipraz showed generally similar time-course responses of drug-metabolizing enzyme mRNAs; little change from control at 6 h followed by significant and maximal increases 12 to 18 h after treatment. Maximal mRNA changes for 1,7-phenanthroline and oltipraz were of similar magnitude and clustered around 4-fold for most enzymes. With the exception of one UGT isozyme (UGT1A1), the elevations in mRNA were blocked by prior administration of actinomycin D, indicative of a transcription-dependent response. Neither tert-butyl-4-hydroxyanisole nor tert-butylhydroquinone caused a statistically significant increase in any mRNA examined at any time point.
 ...
PMID:Early events in the induction of rat hepatic UDP-glucuronosyltransferases, glutathione S-transferase, and microsomal epoxide hydrolase by 1,7-phenanthroline: comparison with oltipraz, tert-butyl-4-hydroxyanisole, and tert-butylhydroquinone. 1095 Aug 43

Conventionally adjustments of the dose of chemotherapeutic treatment could be uneffective in preventing toxicity and response variability. New strategies for individualization of treatment in cancer patients are becoming an emerging issue in the clinical practice. Pharmacogenetics is undoubtedly an important source of information in this respect deepening the complex correlation existing between individual genetic profile and the response to therapy in terms of toxicity and activity. Several polymorphisms, i.e. genetic mutations with a frequency > 1% in a given population, have been described for genes encoding proteins involved in the metabolism of the drugs employed in the treatment of gastric cancer. TS (thymidilate synthase) and DPD (dihydropyrimidine dehydrogenase) polymorphisms are implicated in the development of toxicity and in the efficacy of 5-fluorouracil (5FU). XRCC1 (X-ray cross-complementing group 1), ERCC1 (excision cross-complementing gene) and GSTP1 (glutathione S-transferase) have a role in the development of pharmacoresistance to platinum derivatives. MTHFR (5, 10 methylenetetrahydrofolate reductase) C677T polymorphism is important in methotrexate (MTX) metabolism. UGT1A1 (uridine diphoshate-glucuronosyltransferase 1A1) is involved on irinotecan metabolism. MRP2 (multi-drug resistance associated protein) and MDR1 (multi-drug resistance gene) are involved in irinotecan as well as anthracyclines transport. In conclusion, the clinical applications of pharmacogenetics could represent a new insight to accurately determine the proper drug and dose to be used in each individual patient.
 ...
PMID:Pharmacogenetics of stomach cancer. 1291 84

Colorectal cancer (CRC) is one of the most common malignancies in the Western world showing an increasing incidence, and has been associated with genetic and lifestyle factors. Individual susceptibility to CRC may be due partly to variations in detoxification capacity in the gastrointestinal tract. Genetic polymorphisms in detoxification enzymes may result in variations in detoxification activities, which subsequently might influence the levels of toxic/carcinogenic compounds, and this may influence the risk for CRC. To determine whether genetic polymorphisms in detoxification enzymes predispose to the development of CRC, 371 patients with sporadic CRC and 415 healthy controls were genotyped for polymorphisms in the important detoxification enzymes UDP-glucuronosyltransferase UGT1A1, UGT1A6, UGT1A7 and UGT1A8, and glutathione S-transferase GSTA1, GSTM1, GSTP1 and GSTT1. Patients and controls were all of Caucasian origin. DNA was isolated from either blood or tissue and tested by polymerase chain reaction followed by restriction fragment length polymorphism analyses. Logistic regression analyses showed significant age- and gender-adjusted risks for CRC associated with variant genotypes of UGT1A6 [OR 1.5, 95% (confidence interval) CI 1.03-2.3] and UGT1A7 (OR 2.4, 95% CI 1.3-4.6), whereas no associations were found between CRC and the other polymorphic genes as mentioned above. In conclusion, the data suggest that the presence of variant UGT1A6 and UGT1A7 genotypes with expected reduced enzyme activities, might enhance susceptibility to CRC.
 ...
PMID:Genetic polymorphisms in UDP-glucuronosyltransferases and glutathione S-transferases and colorectal cancer risk. 1531 94

Estrogen has been suggested to trigger breast cancer development via an initiating mechanism involving its metabolite, catechol estrogen (CE). To examine this hypothesis, we carried out a multigenic case-control study of 469 incident breast cancer patients and 740 healthy controls to define the role of important genes involved in the different metabolic steps that protect against the potentially harmful effects of CE metabolism. We studied the 3 genes involved in CE detoxification by conjugation reactions involving methylation (catechol-O-methyltransferase, COMT), sulfation (sulfotransferase 1A1, SULT1A1), or glucuronidation (UDP-glucuronosyltransferase 1A1, UGT1A1), one (manganese superoxide dismutase, MnSOD) involved in protection against reactive oxidative species-mediated oxidation during the conversion of CE-semiquinone (CE-SQ) to CE-quinone (CE-Q), and 2 of the glutathione S-transferase superfamily, GSTM1 and GSTT1, involved in CE-Q metabolism. Support for this hypothesis came from the observations that (i) there was a trend toward an increased risk of breast cancer in women harboring a greater number of putative high-risk genotypes of these genes (p < 0.05); (ii) this association was stronger and more significant in those women who were more susceptible to estrogen [no history of pregnancy or older (> or =26 years) at first full-term pregnancy (FFTP)]; and (iii) the risks associated with having one or more high-risk genotypes were not the same in women having experienced different menarche-to-FFTP intervals, being more significant in women having been exposed to estrogen for a longer period (> or =12 years) before FFTP. Furthermore, because CE-Q can attack DNA, leading to the formation of double-strand breaks (DSB), we examined whether the relationship between cancer risk and the genotypic polymorphism of CE-metabolizing genes was modified by the genotypes of DSB repair genes, and found that a joint effect of CE-metabolizing genes and one of the two DSB repair pathways, the homologous recombination pathway, was significantly associated with breast cancer development. Based on comprehensive CE metabolizing gene profiles, our study provides support to the hypotheses that breast cancer can be initiated by estrogen exposure and that increased estrogen exposure confers a higher risk of breast cancer by causing DSB to DNA.
 ...
PMID:Breast cancer risk associated with genotype polymorphism of the catechol estrogen-metabolizing genes: a multigenic study on cancer susceptibility. 1545 71

UDP-glucuronosyltransferase (UGT) 1A1 glucuronidates endogenous metabolites, such as bilirubin, and exogenous substances, and plays a critical role in their detoxification and excretion. In a previous article, we described the phenobarbital response activity to a 290-base pair (bp) distal enhancer sequence (-3499/-3210) of the human UGT1A1 gene that is activated by the constitutive androstane receptor (CAR). Here, we show that dexamethasone at submicromolar concentrations enhances the pregnane X receptor (PXR) activator-mediated expression of the UGT1A1 gene and protein in HepG2 cells. We investigated the molecular mechanism of UGT1A1 induction by glucocorticoids at submicromolar concentrations and PXR activators and the functional cross-talk between the glucocorticoid receptor (GR) and CAR/PXR. The glucocorticoid-response element (GRE) was characterized by cotransfection experiments, site-directed mutagenesis, and electrophoretic mobility shift assays. Analysis of the human UGT1A1 promoter revealed GREs at -3404/-3389 and -3251/-3236 close to the CAR/PXR response element gtNR1 (-3382/-3367). Furthermore, in an in vitro reporter gene assay, dexamethasone effectively enhanced CAR/PXR-mediated transactivation of the 290-bp distal enhancer module in HepG2 cells and CV-1 cells in the presence of exogenously expressed GR and glucocorticoid receptor-interacting protein 1 (GRIP1). In glutathione S-transferase pull-down experiments, CAR and PXR interacted with GRIP1. Together, these results demonstrate a rational mechanistic basis for UGT1A1 induction by glucocorticoids and PXR activators, showing that activated GR enhances CAR/PXR-mediated UGT1A1 regulation with the transcriptional cofactor GRIP1 and that GR may be involved synergistically in the xenobiotic-responsive regulation of UGT1A1 by CAR/PXR.
 ...
PMID:Transcriptional regulation of human UGT1A1 gene expression: activated glucocorticoid receptor enhances constitutive androstane receptor/pregnane X receptor-mediated UDP-glucuronosyltransferase 1A1 regulation with glucocorticoid receptor-interacting protein 1. 1555 60

The expression level of phase I (CYP1A1 and CYP1A2) and phase II (GST, and UGT) enzyme-coded genes were measured in liver microsomes of 30 Sprague-Dawley rats fed sea weed (Monostroma nitidum). Quantitative and qualitative analysis of the detoxifying enzymes were investigated using reverse transcription polymerase reaction (RT-PCR) and real time polymerase reaction (Real-time PCR) techniques. The antioxidative properties of seaweed were screened and investigated for its hepatoprotective activity in rat. There was no significant induction of GSTYa1, GSTYa2, and CYP1A2. However, an M. nitidum diet was found to significantly increase UGT1A1 and UGT1A6 mRNA levels and to decrease CYP1A1 mRNA levels in rat liver. Structural studies confirmed the presence of sulfated polysaccharides in the seaweed samples. The results demonstrate the potential of seaweed as a natural source of sulfated polysaccharide substances with potential use in chemoprevention medicine.
 ...
PMID:Studies on the expression of liver detoxifying enzymes in rats fed seaweed (Monostroma nitidum). 1767 47

The HepG2 cell line is a valuable tool for screening for cytotoxicity in the early phase of pharmaceutical development. Some compounds which produce reactive and toxic metabolites, are classified as being toxic in HepG2 cells. In contrast, other compounds, which are toxic in primary human hepatocytes, are not toxic in HepG2 cells. A difference in metabolism between HepG2 cells and primary human hepatocytes might be the reason. To investigate this, cytochrome P450 and Phase II enzyme levels were characterized. In the present study the focus is on Phase II enzyme metabolism. Transcript levels of UDP-glucuronosyl transferases (UGTs), sulfotransferases (SULTs), glutathione S-transferases (GSTs), N-acetyltransferase-1 (NAT1) and epoxide hydrolase (EPHX1) were measured with quantitative PCR in HepG2 cells and cryopreserved primary human hepatocytes. Levels of SULT1A1, 1A2, 1E1, 1A2, and 2A1, microsomal GST 1, GST mu1, NAT1, and EPHX1 in HepG2 cells were almost similar to levels in primary human hepatocytes. In contrast, levels of UGT1A1 and 1A6 transcripts were between 10- and more than 1000-fold higher in the primary hepatocytes. The regulatory processes of Phase II enzymes by the aryl hydrocarbon receptor, pregnane X receptor and constitutive androstane receptor were studied in HepG2 cells and appeared quite similar to those in primary human hepatocytes. Due to the involvement of Phase II enzymes in the toxication of some compounds, HepG2 cells can be a valuable cellular system to predict toxicity for these compounds. On the other hand, the normal expression of most Phase II enzymes in combination with the lower expression of cytochrome P450 enzymes in HepG2 cells might result in an underestimation of toxicity for several compounds. Compared to primary human hepatocytes, HepG2 cells are a relatively easy-to-handle tool to study the up-regulation of Phase II enzymes.
 ...
PMID:Phase II enzyme levels in HepG2 cells and cryopreserved primary human hepatocytes and their induction in HepG2 cells. 1771 55

We reported earlier that exposure of rats to 3-methylcholanthrene (MC) causes sustained induction of hepatic cytochrome P450 (CYP)1A expression for up to 45 days by mechanisms other than persistence of the parent MC (Moorthy, J. 2000. Pharmacology. Exp. Ther. 294, 313-322). The CYP1A genes are members of the Ah gene battery that also encode CYP1B1 and phase II enzymes such as glutathione S-transferase (GST-alpha), UDP glucuronyl transferase (UGT)1A, NAD(P)H (nicotinamide adenine dinucleotide phosphate, reduced):quinone oxidoreductase I (NQO1), aldehyde dehydrogenase (ALDH), etc. Therefore, in this investigation, we tested the hypothesis that MC elicits persistent induction of CYP1B1 and phase II genes, which are in part regulated by the Ah receptor (AHR). Female Sprague-Dawley rats were treated with MC (100 mumol/kg), ip, once daily for 4 days, and expression of CYP1B1 and several phase II (e.g., GST-alpha, NQO1) genes and their corresponding proteins were determined in lung and liver. The major finding was that MC persistently induced (3- to 10-fold) the expression of several phase II enzymes, including GST-alpha, NQO1, UGT1A1, ALDH, and epoxide hydrolase in both tissues for up to 28 days. However, MC did not elicit sustained induction of CYP1B1. Our results thus support the hypothesis that MC elicits coordinated and sustained induction of phase II genes presumably via persistent activation of the AHR, a phenomenon that may have implications for chemical-induced carcinogenesis and chemopreventive strategies in humans.
 ...
PMID:Persistent induction of hepatic and pulmonary phase II enzymes by 3-methylcholanthrene in rats. 1820 89

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.
 ...
PMID:Effect of breed upon cytochromes P450 and phase II enzyme expression in cattle liver. 1826 77


1 2 Next >>