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)

This study analyses the expression and induction of several drug-metabolising enzyme activities involved in either phase I or phase II biotransformations in NCTC 2544 human keratinocytes. The phase I activities 7-ethoxycoumarin O-deethylase (ECOD), 7-ethoxyresorufin O-deethylase (EROD) and 7-pentoxyresorufin O-depenthylase (PROD) were easily detectable in basal conditions. During incubations lasting up to 144 h in the presence of the classical cytochrome P450 inducers beta-naphthoflavone (BNF), 3-methylcholanthrene (MC) and phenobarbital (PB), a considerable and significant increase in all the three activities was observed. PROD activity was induced up to 4.5-fold after 96 h in the presence of PB. The MC-induced ECOD and EROD activities were also dose-dependently inhibited by alpha-naphothflavone, which was given to the cells during the incubation with CYP 1A1 inducers. Also the PB-induced PROD activity was decreased by the simultaneous addition of the CYP 2B inhibitor metyrapone. Both cytochrome P450 inhibitors were used at non-cytotoxic concentrations. The phase II enzymes glutathione S-transferase, aldehyde dehydrogenase and quinone reductase were all highly expressed and inducible by MC. The exposure (24 h) of the cells to four hair dyes used in cosmetic formulations resulted in a marked increase in ECOD activity. All data give sustained evidence for the suitability of NCTC 2544 cell line to skin toxicology studies.
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PMID:Induction by xenobiotics of phase I and phase II enzyme activities in the human keratinocyte cell line NCTC 2544. 1169 72

The effects of turmeric feeding before and after benzo(a)pyrene [B(a)P] exposure on the levels of B(a)P-derived DNA adducts were studied in tissues of Swiss mice employing (32)P-postlabelling analysis. A reduction in the levels of B(a)P-derived DNA adducts in liver, lung, and forestomach was observed in animals pre-treated with 0.2 or 1% turmeric diet and exposed to B(a)P by oral intubation when compared to animals receiving standard laboratory diet and B(a)P. The observed decrease was not due to dilution caused by nascent DNA synthesis. Comparative evaluation of levels of B(a)P-derived DNA adducts in tissues of animals shifted to 0.2 or 1% turmeric diet after 24 h of oral intubation of B(a)P with those continued on standard laboratory diet did not suggest enhanced disappearance/repair of B(a)P-derived DNA adducts due to exposure to turmeric. Further, pre-treatment of mice with 1% turmeric diet significantly reduced the B(a)P-induced increase in activity of cytochrome P450 (CYP450) isozymes CYP 1A1 and 1A2 in liver, lung, and forestomach of mice. In addition, hepatic glutathione S-transferase (GST) was found to be elevated in turmeric pre-treated mice. Thus turmeric-mediated decrease in induction of phase-I enzymes in liver, lung, and forestomach of mice and enhancement of hepatic GST appear to play an important role in reducing the B(a)P-induced DNA damage in target and non-target tissues.
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PMID:Mechanism(s) of turmeric-mediated protective effects against benzo(a)pyrene-derived DNA adducts. 1173 39

The objective of this study was to compare the modulatory effect of garlic oil and its three organosulfur compounds, diallyl sulfide (DAS), diallyl disulfide (DADS), and diallyl trisulfide (DATS), on rat hepatic detoxification enzyme activity, and protein and mRNA expression. Rats were orally administered garlic oil (80 or 200 mg/kg bw), DAS (20 or 80 mg/kg bw), DADS (80 mg/kg bw), or DATS (70 mg/kg bw) three times a week for 6 weeks. Control rats received corn oil. According to the results, garlic oil and DAS in dosages of 200 and 80 mg/kg bw, respectively, significantly increased pentoxyresorufin O-dealkylase (PROD) activity as compared with the that of the control rats (P < 0.05). In contrast, N-nitrosodimethylamine demethylase activity in rats that received DADS and DATS was significantly lower than that in the control rats (P < 0.05). Ethoxyresorufin O-deethylase and erythromycin demethylase activities were not influenced by garlic oil, DAS, DADS, or DATS. To the phase II enzyme, garlic oil, DADS, and DATS significantly increased the glutathione S-transferase (GST) activity toward ethacrynic aicd (P < 0.05). Immunoblot assay showed that the protein contents of cytochrome P450 1A1, 2B1, and 3A1 were increased by garlic oil and each of three allyl sulfides, and the change among the allyl sulfides was in the order of DAS > DADS > DATS. The placental form of GST (PGST) level was also increased by garlic oil and the three allyl sulfides, but the increase among the allyl sulfides was DATS congruent with DADS > DAS. P450 2E1, however, was suppressed by each garlic component. Northern blot results indicated that the changes in P450 1A1, 2B1, 3A1, and PGST mRNA levels by garlic components were similar to those noted in the protein levels. These results indicate that the modulatory effect of garlic oil on hepatic drug-metabolizing enzymes can be attributed to its three major allyl sulfide components DAS, DADS, and DATS. These three allyl sulfides vary in modulatory activity, and this variation is related to the number of sulfur atoms in the molecule.
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PMID:Differential effects of garlic oil and its three major organosulfur components on the hepatic detoxification system in rats. 1178 11

AIM:The food-borne carcinogen 2-amino-1-methyl-6-phenylimidazo 4,5-b pyridine (PhIP) induces colon and mammary gland tumors in rats and has been implicated in the etiology of human colorectal cancer.This study was conducted to examine the potentially preventive effect of Chinese cabbage (Brassica chinensis),a brassica vegetable most commonly consumed in China, against this carcinogen-induced DNA adduct formation in rats and its possible mechanisms.METHODS:Sprague-Dawley rats were maintained for 10 days on basal diet or diet containing 20% (w/w) freeze-dried cabbage powder prior to administration of a single dose of PhIP (10mg/kg) by oral gavage. Rats were sacrificed at 20h after PhIP treatment and PhIP-DNA adducts in the colon, heart, lung and liver were analyzed using (32)P-postlabeling technique. Levels of hepatic cytochrome P450 (CYP)1A1 and 1A2, as indicated by 7-ethoxyresorufin O-deethylase and 7-methoxyresorufin O-demethylase activity, and cytosolic glutathione S-transferases (GSTs) towards 1-chloro-2, 4-dinitrobenzene (CDNB) in the liver, lung and colon were measured.RESULTS:Rats pre-treated with Chinese cabbage and given a single dose of PhIP had reduced levels of PhIP-DNA adducts in the colon, heart, lung and liver, with inhibition rates of 82.3%, 60.6%, 48.4% and 48.9%, respectively (P< 0.01). The enzyme assays revealed that Chinese cabbage induced both CYP1A1 and 1A2 activity, but the induction was preferential for CYP1A1 over 1A2 (81% vs 51%).GST activity towards CDNB in the liver and lung, but not colon, was also significantly increased by cabbage treatment.CONCLUSION:The results indicate that Chinese cabbage has a preventive effect on PhIP-initiated carcinogenesis in rats and the mechanism is likely to involve the induction of detoxification enzymes.
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PMID:Chemoprevention of 2-amino-1-methyl-6-phenyli-midazo 4,5-b pyridine-induced carcinogen-DNA adducts by Chinese cabbage in rats. 1181 13

Genetic polymorphisms involved in the activation and detoxification of exogenous chemicals and in the production and scavenging of reactive oxygen species may modulate the levels of oxidative injury biomarker. We investigated 81 pregnant women in Inchon, Korea. In addition to a questionnaire survey, urinary concentrations of 8-hydroxydeoxyguanosine (8-OH-dG) and malondialdehyde (MDA) were measured as oxidative injury biomarkers. Cytochrome P-450(CYP)1A1, CYP2E1, glutathione S-transferase (GST)M1 and GSTT1 polymorphisms and myeloperoxidase (MPO) and manganese superoxide dismutase (MnSOD) polymorphisms were evaluated to determine the effect of genetic modification on urinary 8-OH-dG and MDA. The concentrations of urinary 8-OH-dG were significantly elevated in the presence of the MnSOD variant genotype (P=0.04) and in the case of GSTM1 null status (P=0.02) by multivariate regression. The concentrations of urinary MDA were not affected significantly by the genetic polymorphisms. This result shows that oxidative stress injury is modified by some heritable polymorphisms, including GSTM1 and MnSOD.
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PMID:Genetic susceptibility of term pregnant women to oxidative damage. 1188 9

There is growing interest in the potential health benefits of tea, including the anticarcinogenic properties. We report here that white tea, the least processed form of tea, is a potent inhibitor of 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP)-induced colonic aberrant crypts in the rat. Male Fischer 344 rats were treated for 8 wk with white tea (2% wt/vol) or drinking water alone, and on alternating days in experimental Weeks 3 and 4 the animals were given PhIP (150 mg/kg body wt p.o.) or vehicle alone. At the end of the study there were 5.65 +/- 0.81 and 1.31 +/- 0.27 (SD) aberrant crypt foci per colon in groups given PhIP and PhIP + white tea, respectively (n = 12, P < 0.05). No changes were detected in N-acetyltransferase or arylsulfotransferase activities compared with controls, but there was marked induction of ethoxyresorufin O-deethylase, methoxyresorufin O-demethylase, and UDP-glucuronosyltransferase after treatment with white tea. Western blot revealed corresponding increases in cytochrome P-450 1A1 and 1A2 proteins. Enzyme assays and Western blot also revealed induction of glutathione S-transferase by white tea. There was less parent compound and 4'-hydroxy-PhIP but more PhIP-4'-O-glucuronide and PhIP-4'-O-sulfate in the urine from rats given PhIP + white tea than in urine from animals given carcinogen + drinking water. The results indicate that white tea inhibits PhIP-induced aberrant crypt foci by altering the expression of carcinogen-metabolizing enzymes, such that there is increased ring hydroxylation at the 4' position coupled with enhanced phase 2 conjugation.
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PMID:Inhibition by white tea of 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine-induced colonic aberrant crypts in the F344 rat. 1209 35

Our groups have had a long-term interest in utilizing bacterial systems in the characterization of bioactivation and detoxication reactions catalyzed by cytochrome P450 (P450) and glutathione transferase (GST) enzymes. Bacterial systems remain the first choice for initial screens with new chemicals and have advantages, including high-throughput capability. Most human P450s of interest in toxicology have been readily expressed in Escherichia coli with only minor sequence modification. These enzymes can be readily purified and used in assays of activation of chemicals. Bicistronic systems have been developed in order to provide the auxiliary NADPH-P450 reductase. Alternative systems involve these enzymes expressed together within bacteria. In one approach, a lac selection system is used with E. coli and has been applied to the characterization of inhibitors of P450s 1A2 and 1B1, as well as in basic studies involving random mutagenesis. Another approach utilizes induction of the SOS (umu) response in Salmonella typhimurium, and systems have now been developed with human P450s 1A1, 1A2, 1B1, 2C9, 2D6, 2E1, and 3A4, which have been used to report responses from heterocyclic amines. S. typhimurium his reporter systems have also been used with GSTs, first to demonstrate the role of rat GST 5-5 in the activation of dihalomethanes. These systems have been used to compare these GSTs with regard to activation of dihaloalkanes and potential toxicity.
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PMID:Use of heterologously-expressed cytochrome P450 and glutathione transferase enzymes in toxicity assays. 1250 22

Polychlorinated biphenyls (PCBs) have been shown to be embryotoxic. The mechanism(s) of action is not clearly understood. The toxic effects could be either direct or indirect. Furthermore, PCB congeners vary in their toxic potential. They can be classified in coplanar PCBs binding to the transcription factor aryl hydrocarbon receptor (AhR), which induce subsequent changes in gene expression, and noncoplanar PCBs exhibiting AhR-independent effects. In order to investigate possible mechanisms, 5 and 6 days old preimplantation rabbit embryos were exposed in vitro to low levels of coplanar (PCB 77, 126, and 169) or noncoplanar PCBs (PCB 28, 52, 101, 118, 138, 153, and 180). The PCB effects were studied by semiquantitative RT-PCR analysis of AhR target genes (cytochrome P450 (CYP) 1A1, 1A2, UDP-glucuronosyl transferase 1, glutathione S-transferase pi1 and aldehyde dehydrogenase) and dioxin-responsive genes (IL 1beta, PAI 2, Cox 2, TGFalpha, EGF, erbB 1-4, c-fos, c-jun, HSP 90, cyclophilin 40), and by differential display (DD) RT-PCR. CYP 1B1 mRNA and AhR protein were localized by in situ hybridization and immunohistochemistry, respectively. From the AhR target genes studied only CYP 1B1, and cyclooxygenase 2 showed an increase in mRNA levels after coplanar and noncoplanar PCB. Interleukin 1beta and plasminogen activator inhibitor 2 were downregulated. CYP 1B1 mRNA showed a stage specific inducibility at day 6, but not at day 5. By DD RT-PCR we identified six new genes previously not reported to be regulated by PCBs. The mRNAs encoding the subunits 1, 2, 4, and 5 of the NADH ubiquinone oxidoreductase and beta-globin showed a decrease, whereas trichohyalin mRNA was increased after PCB exposure. Coplanar and noncoplanar PCB congeners elicited similar responses on the mRNA levels of the studied genes. Exposure to coplanar PCBs did not result in the AhR being translocated to the nucleus. Our results show that (i). PCBs induce changes in gene expression in rabbit day 5 and 6 preimplantation embryos and imply (ii). that the transcriptional changes observed were not mediated by the nuclear AhR.
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PMID:Polychlorinated biphenyls affect gene expression in the rabbit preimplantation embryo. 1254 57

This present study was designed to investigate the combined modulatory effect of garlic oil (GO) and fish oil (FO) on the antioxidant and drug metabolism systems. Rats were fed either a low-maize oil (MO) diet (50 g MO/kg), high-MO diet (235 g MO/kg) or high-FO diet (205 g FO+ 30 g MO/kg) and received different doses of GO (0-200 mg/kg body weight) three times per week for 6 weeks. Fatty acid analysis showed that 20 : 5n-3 and 22 : 6n-3 were incorporated into serum lipid at the expense of 18 : 2n-6 and 20 : 4n-6 in rats fed the high-FO diet. GO dose-dependently increased hepatic glutathione S-transferase (GST), glutathione reductase, superoxide dismutase (SOD) and ethoxyresorufin O-deethylase (EROD) activities, but decreased glutathione peroxidase and N-nitrosodimethylamine demethylase (NDMAD) activities (P<0.05). With the exception of glutathione peroxidase, the activities of glutathione reductase, SOD, GST, EROD and NDMAD were modulated by the dietary fat. The high-FO group had greater SOD and EROD activity than either MO-fed group; it also had greater NDMAD activity than the low-MO group (P<0.05). GST activity was higher in rats fed high-FO or high-MO diets than rats fed the low-MO diet. Change in erythromycin demethylase activity, however, was not caused by either dietary fat or GO. Immunoblot assay showed that GO dose-dependently enhanced the protein level of the Ya, Yb1, Yc isoenzymes of GST and cytochrome P450 (CYP) 1A1 and 3A1, but GO suppressed CYP2E1 expression. Regardless of the dosage of GO, the high-FO diet increased CYP1A1, CYP3A1 and CYP2E1 levels compared with the high- and low-MO diets. Accompanying the changes observed in immunoblots, CYP1A1 and CYP3A1 mRNA levels were increased by GO in a dose-dependent manner and also increased additively in combination with FO feeding. These present results indicate that co-administration of GO and FO modulates the antioxidant and drug-metabolizing capacity of animals and that the effect of GO and FO on drug-metabolizing enzymes is additive.
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PMID:The combined effects of garlic oil and fish oil on the hepatic antioxidant and drug-metabolizing enzymes of rats. 1257 3

Although diesel exhaust particles (DEP) are known to produce pulmonary disorders, the xenobiotic metabolic pathways associated with DEP detoxification and bioactivation remain unclear. In this study, the effect of acute exposure of DEP on phase I and phase II enzymes of rat lung was investigated. Intratracheal administration of DEP produced an induction of cytochrome P-450 (CYP) 1A1 enzyme protein and activity at 1 d postexposure, with the enzyme level returning to control at 5 d postexposure. On the other hand, carbon black (CB), a particle control, did not show any induction of CYP1A1 protein or enzyme activity. However, both DEP and CB significantly decreased CYP2B1 protein and enzyme activity at 1 d postexposure. The decrease in CYP2B1 enzyme protein and activity by DEP or CB treatment was observed up to 7 d postexposure. DEP and CB treatments also significantly attenuated glutathione S-transferase (GST)-pi protein at 1 d postexposure. Both DEP and CB at 35 mg/kg significantly decreased the activities of GST and catalase at 1 and 7 d postexposure. DEP, but not CB, significantly induced quinone reductase (QR) activity at 7 d postexposure. This study suggests that DEP may induce CYP1A1 and QR enzymes via a chemical effect, while the carbonaceous core may be involved in the attenuation of CYP2B1, GST, and catalase proteins and enzyme activities.
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PMID:Diesel exhaust particle-induced alterations of pulmonary phase I and phase II enzymes of rats. 1265 20


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