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)

Phenethyl isothiocyanate (PEITC), a constituent of cruciferous vegetables, has been shown to inhibit chemical carcinogenesis, possibly due to its ability to block the activation or to enhance the detoxification of chemical carcinogens. The present study was conducted to elucidate the biochemical mechanisms involved by characterizing the effects of PEITC on phase I and phase II xenobiotic-metabolizing enzymes. A single dose of PEITC to F344 rats (1 mmol/kg) decreased the liver N-nitrosodimethylamine demethylase (NDMAd) activity (mainly due to P450 2E1) by 80% at 2 h and the activity of NDMAd remained decreased by 40% at 48 h after treatment. The liver pentoxyresorufin O-dealkylase (PROD) activity and P450 2B1 protein level were elevated 10- and 7-fold at 24 h after treatment respectively. The liver microsomal ethoxyresorufin O-dealkylase (EROD) (mainly due to P450 1A) and erythromycin N-demethylase (mainly due to P450 3A) activities were decreased at 2-12 h after treatment and recovered afterwards. The lung microsomal PROD and EROD activities were not significantly affected; whereas, the nasal microsomal PROD and EROD activities were decreased by 40-50%. After a treatment with PEITC, the rates of oxidative metabolism of 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) were decreased in liver microsomes by 40-60% at 2 h and recovered gradually; the rates in lung microsomes were markedly decreased by 60-70% at 2 h and remained at the decreased level at 24 h; and the rates in nasal mucosa microsomes were decreased gradually with the lowest activities observed at 18 h (50%) followed by a gradual recovery. Furthermore, the treatment with PEITC resulted in a maximal 5-fold increase of NAD(P)H:quinone oxidoreductase and 1.5-fold increase of glutathione S-transferase activities in the liver, but the activities of these two enzymes were not significantly affected in the lung and nasal mucosa. The sulfotransferase activity in the liver was decreased by 32-48% at 24-48 h after treatment; the nasal activity was increased by 1.8- to 2.5-fold, but the lung activity was not significantly changed. The hepatic UDP glucuronosyltransferase activity was slightly decreased at 2 h but slightly increased at 48 h after treatment, but no changes were observed for the lung and nasal activities. The study demonstrates that PEITC selectively affects xenobiotic-metabolizing enzymes in the liver, lung and nasal mucosa and it is especially effective in inhibiting the P450-dependent oxidation of NNK in the lung and of NDMA in the liver.
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PMID:Effects of phenethyl isothiocyanate, a carcinogenesis inhibitor, on xenobiotic-metabolizing enzymes and nitrosamine metabolism in rats. 147 25

Three indole antioxidants were compared for their efficacy to inhibit lipid peroxidation, prevent chemical hepatotoxicity and induce enzyme systems involved in the biotransformation of xenobiotics. The dietary indolyl compound indole-3-carbinol (I-3-C), and the synthetic compounds 5,10-dihydroindeno[1,2-b]-indole (DHII) and 4b,5,9b,10-tetrahydroindeno[1,2-b]indole (THII) inhibited carbon tetrachloride (CCl4)-initiated lipid peroxidation in rat-liver microsomes, with the order of efficacy THII greater than DHII = butylated hydroxytoluene (BHT) much greater than I-3-C. Each of the indole compounds protected isolated rat hepatocytes against toxicity by CCl4, N-methyl-N'-nitro-N-nitrosoguanidine and methylmethanesulphonate (THII congruent to DHII much greater than I-3-C). In vivo administration of the indole compounds 1 hr before treatment with CCl4 protected against hepatotoxicity (THII greater than DHII greater than I-3-C). For the enzyme induction studies, phenobarbital and beta-naphthoflavone were used as standards, with corn-oil vehicle controls. The compounds were administered by gavage at 50 mg/kg body weight/day for 10 days. I-3-C produced increases in levels of hepatic cytochromes P-450 and ethoxyresorufin O-deethylase (EROD) activity, as well as in UDP-glucuronosyl transferase (UDPGT), glutathione S-transferase (GST), glutathione reductase (GSSG-Red) and quinone reductase. I-3-C produced decreased glutathione peroxidase (GSH-Px) and superoxide dismutase (SOD) activities. DHII produced increases in EROD, UDPGT, GST, GSSG-Red and quinone reductase, with decreases in NDMA-demethylase and GSH-Px activities. The only observed effect of THII was a modest induction of EROD activity. After treatment with the indole compounds for 10 days, I-3-C enhanced, while DHII diminished, CCl4-mediated 24-hr hepatotoxicity in rats. We conclude that DHII and THII are suitable candidates to develop further as potential chemoprotective and therapeutic agents for use in humans to treat disorders involving free radicals. THII has the greater radical scavenging efficacy, whereas DHII has the greater capacity to induce many different antioxidative enzymes.
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PMID:Chemoprotective and hepatic enzyme induction properties of indole and indenoindole antioxidants in rats. 187 67

1. The effects of garlic oil (GO) on the expression of P4502E1, glutathione S-transferase (GST) and microsomal epoxide hydrolase (mEH) were assessed by metabolic activities, immunoblot and RNA blot analyses in the rat. 2. p-Nitrophenol (PNP) hydroxylase activity decreased in the hepatic microsomes isolated from rats treated with GO at 200 mg/kg b.w. by 10-30% as compared with control. Pyrazine-inducible P4502E1 expression was decreased by approximately 40% following concomitant treatment of animals with GO at the dose of 200 mg/kg from day 1 to 3 post-treatment, as evidenced by PNP hydroxylase activity. The rates of aniline hydroxylase and NDMA demethylase activities in GO-treated animals were consistent with those of PNP hydroxylase activity. Treatment of animals with 500 mg/kg GO resulted in suppression of P4502E1-mediated catalytic activities, as monitored by both PNP and aniline hydroxylase activities, whereas the effects at the dose of 1000 mg/kg were identical with those at 500 mg/kg b.w. 3. Immunoblot analyses of hepatic microsomes, using an anti-P4502E1 antibody, showed that GO minimally suppressed constitutive P4502E1 expression at 24, 48 and 72 h post-treatment at the daily doses from 200 to 1000 mg/kg b.w., as compared with vehicle-treated animals. Time-dependent pyrazine induction of P4502E1, however, was substantially blocked by concomitant treatment of animals with 200 mg/kg GO to the levels of control. Treatment at the dose of 1000 mg/kg failed to further suppress P4502E1 levels. GO treatment caused no changes in the levels of P4502E1 mRNA, as assessed by slot blot analyses. 4. Cytosol produced from the GO-treated rat showed approximately 40% increases in GST conjugating activity toward 1-chloro-2,4-dinitrobenzene, whereas mEH protein levels were 1.5-2.0-fold greater than control with similar increases in the mRNA levels noted. 5. These results demonstrate that GO suppresses inducible P4502E1 expression more significantly than constitutive expression, and that GO induces GST and mEH expression to a certain extent.
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PMID:Effects of garlic oil on rat hepatic P4502E1 expression. 857 58

Polycyclic aromatic hydrocarbons (PAHs) and N-nitrosamines (NNA) are mainly activated by cytochrome P450s, and their associated enzyme activities such as aryl hydrocarbon (benzo(a)pyrene) hydroxylase (AHH), N-nitrosdimethylamine N-demethylase I (NDMA-dI), NADPH-cytochrome C reductase, and detoxified by glutathione S-transferase (GST) and glutathione (GSH). The present study shows the influence of Cymbopogon proximus (Halfa barr), Zygophyllum coccineum L. (Kammun quaramany), Lupinus albus (Termis) as herbs capable of inducing hypoglycemia on the activity of the above mentioned enzymes in the liver of diabetic rats. Alloxan was administered as a single dose (120 mg/kg body weight) to induce diabetes and the herbs were administered to diabetic rats as repeated doses for 4 weeks. Alloxan-induced diabetes significantly increased the blood glucose level by 93% compared to the control level. On the other hand, repeated-dose treatments of diabetic rats with Cymbopogon proximus and Lupinus albus are more effective than Zygophyllum coccineum in restoring the elevated blood glucose level to the normal level. Alloxan treatment increased the hepatic activity of cytochrome P450, NADPH-cytochrome C reductase, AHH, NDMA-dI, GST and GSH by 112, 122, 82, 99, 64 and 26%, respectively. These herbs decreased the activity of above mentioned enzymes in the liver of diabetic rats compared to alloxan-treated rats. We conclude that alloxan increased the activity of cytochrome P450 system and that such herbs reduced these activities. The toxic effects of PAHs (e.g. benzo(a)pyrene) and NNA (e.g. N-nitrosdimethylamine) could be increased in the liver of diabetic rats through induction of their corresponding bioactivating enzymes. On the other hand, hypoglycemic herbs could alleviate the deleterious effects of these carcinogens in the liver of diabetic rats since these herbs reduced the hepatic content of cytochrome P450 and other associated enzyme activities compared to the diabetic group. Such alterations in the activity of phase I and II drug-metabolizing enzymes should be considered when therapeutic drugs are administered to diabetic patients since most of drugs are metabolized mainly by the cytochrome P450 system.
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PMID:Effect of some hypoglycemic herbs on the activity of phase I and II drug-metabolizing enzymes in alloxan-induced diabetic rats. 1198 90

The mixed function oxidase system includes the phase I drug oxidation proteins e.g. aryl hydrocarbon hydroxylase (AHH), N-nitrosodimethylamine-N-demethylase I (NDMA-dI) and cytochrome b5 which metabolize most carcinogens and xenobiotics into less and/or more active intermediates. These were determined in human bladder tissues diagnosed as bladder cancer only (10 samples) and bladder cancer associated with Schistosoma haematobium (12 samples) and normal bladder tissues (12 samples). In addition to the above enzymes, agents involved in Phase II drug metabolism e.g. glutathione and glutathione S-transferase as well as free radicals (detected as thiobarbituric acid-reactive substances, TBARS) were also determined in these tissues samples. AAH and NDMA-dI, cytochrome b5, and glutathione S-transferase activity decreased by 42, 28, 47 and 32%, respectively, in human bladder cancer tissues. In bladder cancer tissues associated with S. haematobium infection NDMA-dI and GST activity decreased further by 65 and 56%, respectively, whereas AHH activity increased by 50% and levels of reduced glutathione also increased by 43% in cancer tissue and by 29% in schistocome infected bladder cancer tissue. The level of free radicals also increased significantly (by 57%) in infected bladder cancer tissue but not at all in non-infected cancer tissue. Alterations in the activity of phase I and II of drug-metabolizing enzymes in human bladder tissues as a result of S. haematobium infection may therefore change the bladder's capacity to detoxify many endogenous compounds and may also potentiate the deleterious effects of bladder carcinogens, (e.g. N-nitrosamines) which are known to be present in relatively large quantities in the bladder of patients with schistosomiasis. The present study thus provides new insights into mechanisms for the genesis of bladder cancer initiated in association with schistosomiasis.
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PMID:Effects of Schistosoma haematobium infection on drug-metabolizing enzymes in human bladder cancer tissues. 1503 56

Dwarf nettle (Urtica urens) seed extract was examined in vivo in the rat for its potential to modulate drug metabolizing enzymes including aminopyrine N-demethylase (APND; CYP2C6), aniline 4-hydroxylase (A4H; CYP2E1), nitrosodimethylamine N-demethylase (NDMA-ND; CYP2E1) erythromycin N-demethylase (ERND; CYP3A1) CYP2D1/2 and glutathione S-transferase (GST). RT-PCR data and western blotting studies clearly demonstrated that CYP2C6 and CYP2E1 mRNA levels were substantially increased after Urtica treatment, while the level of CYP3A1 mRNA decreased and that of CYP2D1/2 remained unchanged. Urtica treatment significantly induced GST activity in the liver, lung and kidney (66-, 46- and 31-fold, respectively) while decreasing that of APND (35-, 61- and 94-fold) and NDMA-ND (23, 28 and 54-fold). ERND activity in liver was reduced 45-fold, but increased in the lung and kidney (78- and 144-fold) after Urtica treatment. These results indicate that Urtica seed extract may have the potential to inhibit and/or induce the metabolism of certain co-administered drugs.
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PMID:Drug interaction potential of the seed extract of Urtica urens L. (dwarf nettle). 1944 Oct 62