Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: EC:1.6.5.2 (NQO1)
 6,196 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

1. The chemical reactivity of bromobenzene metabolite(s) responsible for its protein covalent binding was investigated by determining the effects of many chemical and enzymic probes on the metabolism and covalent binding of [3,5-3H]bromobenzene with rat liver microsomes in vitro. 2. Classical cytochrome P-450 enzyme inhibitors decreased both metabolism and binding in parallel, whereas scavenging agents for reactive oxygen species and free radicals exhibited little or no effect. Sulphur nucleophiles were extremely efficient in decreasing binding with little or no effect on metabolism. Reducing agents such as ascorbate and diaphorase decreased binding slightly more than metabolism. 3. UDP-Glucuronic acid inhibited neither metabolism nor binding, but all three mono-bromophenols decreased binding more than metabolism. Trichloropropene oxide was unique in decreasing metabolism more than binding. 4. The effects of ascorbate, glutathione, bisulphite and butylated hydroxytoluene (BHT) on metabolism and binding of five ortho-substituted bromobenzene derivatives (o-BrC6H4X; X = OCH3, CH3, Br, CF3, and CN) were similar to their effects on the metabolism and binding of bromobenzene. 5. Collectively these results support a major role for quinones as the reactive metabolites responsible for the majority of the protein covalent binding of bromobenzene and its ortho-substituted derivatives in microsomal systems in vitro.
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PMID:Effects of chemical and enzymic probes on microsomal covalent binding of bromobenzene and derivatives. Evidence for quinones as reactive metabolites. 340 Feb 72

Hepatocarcinogens cause marked biochemical changes in the liver at short intervals after administration. The studies described were designed to investigate the effects of hepatocarcinogens and hepatotoxicants on the microsomal mixed function oxidase system. DT-diaphorase and epoxide hydrolase. Following 5 day p.o. treatment of male F-344 rats with aflatoxin B1 (AFB), 2-acetylaminofluorene (AAF), technical grade dinitrotoluene (DNT), or 2,4-diaminotoluene, microsomal cytochrome P450 dependent enzyme activities were depressed while epoxide hydrolase activity was markedly elevated (3-8 times control). Diethylnitrosamine (DEN) given at 5 mg/kg/day and DL-ethionine at 1000 mg/kg/day failed to increase epoxide hydrolase. 3-Methylcholanthrene, methylnitrosourea, carbon tetrachloride, bromobenzene and vinyl chloride all failed to increase epoxide hydrolase activity. Using 3 daily i.p. injections, dose-response relationships for increases in epoxide hydrolase were generated for the hepatocarcinogens. With the exception of p-dimethylaminoazobenzene (DAB) and DEN, the carcinogens studied produced log-linear dose response curves for increase in epoxide hydrolase. Both DEN and DAB caused increases in epoxide hydrolase but classical sigmoidal dose-response curves were not obtained. The order of potency for increasing epoxide hydrolase was AFB greater than AAF greater than 2,6-dinitrotoluene greater than 3'-methyl-N,N-dimethyl-4-aminoazobenzene greater than DNT greater than 2, 4-dinitrotoluene. The slopes of the linear portions of the log dose-response curves were not statistically different from the slope of the dose-response curve obtained with AAF suggesting that structurally diverse carcinogens elicit increases in epoxide hydrolase by a common mechanism.
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PMID:Effect of hepatocarcinogens on epoxide hydrolase and other xenobiotic metabolizing enzymes. 711 69

We have previously shown that oleanolic acid (OA) protects mice against the hepatotoxicity of carbon tetrachloride, acetaminophen, bromobenzene, thioacetamide, furosemide, phalloidin, colchicine, cadmium, D-galactosamine and endotoxin. This study was designed to examine whether OA modulates hepatic toxicant-activating and detoxifying systems as a means of protection. Mice were treated with OA (100 and 200 mumol/kg s.c.) for 3 days, and liver microsomes and cytosols were prepared 24 hr after the last dose. OA produced a dose-dependent reduction in liver microsomal cytochrome P450 (P450) levels (25-37%) and cytochrome b5 (15-21%) content, but had no effect on NADPH-cytochrome c reductase activity. OA treatment also decreased several P450 enzyme activities, such as coumarin 7-hydroxylation (45%), 7-pentoxyresorufin O-dealkylation (35%), 7-ethoxyresorufin O-dealkylation (25%) and chlorzoxazone 6-hydroxylation (20%). Treatment of mice with OA decreased caffeine N3-demethylation (40%), but had no effect on caffeine 8-hydroxylation. OA treatment decreased testosterone 6 alpha- and 15 alpha-hydroxylation (40-50%) and androstenedione formation (35%), but slightly increased testosterone 1 alpha/beta-, 2 beta- and 6 beta-hydroxylation. Consistent with enzyme activities, OA decreased the amounts of mouse liver CYP1A and CYP2A enzymes, but had no appreciable effect on CYP3A enzymes, as determined by immunoblotting with antibodies against rat P450 enzymes. OA treatment slightly increased liver glutathione (GSH) content and the activity of GSH S-transferases toward 1-chloro-2,4-dinitrobenzene, but had no effect on GSH peroxidase and GSH reductase. The activities of superoxide dismutase and DT-diaphorase were unaffected by OA treatment. At the high dose of OA, catalase activity was decreased by 20%.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Effect of oleanolic acid on hepatic toxicant-activating and detoxifying systems in mice. 747 65

Recent metabolic studies have demonstrated the importance of reactive intermediates like quinones or semiquinone radicals in the covalent binding of halobenzenes to liver protein. The current studies were designed to examine if quinone intermediates are involved in the toxicity of hepatotoxic halobenzenes, bromobenzene (BB) and 1,2,4-trichlorobenzene (1,2,4-TCB). Two-electron reduction of the quinone intermediates by DT-diaphorase is considered to be a detoxication pathway since the resulting hydroquinone may be readily conjugated and excreted. Mice were pretreated with butylated hydroxyanisole (BHA; 0.5% in the diet, for 3 days), an inducer of DT-diaphorase, or dicoumarol (0.3 mmol/kg, p.o.), an inhibitor of this enzyme. The mice were then given BB (2.5 or 3.5 mmol/kg, i.p.) or 1,2,4-TCB (0.75 or 1.5 mmol/kg, i.p.). Dietary BHA markedly suppressed the hepatotoxicity caused by both BB and 1,2,4-TCB while dicoumarol significantly enhanced it, as judged by serum alanine aminotransferase activity. When mice were treated with BB at different times after the end of dietary BHA exposure, the degree of the protection against the hepatotoxicity appears to correlate to the extent of the induction of DT-diaphorase activity by BHA pretreatment. BHA pretreatment failed to protect against carbon tetrachloride-induced hepatotoxicity. These results seem to provide evidence for the involvement of the quinone metabolites in BB- and 1,2,4-TCB-induced hepatotoxicity and for the protective role of DT-diaphorase against the toxicity.
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PMID:Modulation of halobenzene-induced hepatotoxicity by DT-diaphorase modulators, butylated hydroxyanisole and dicoumarol: evidence for possible involvement of quinone metabolites in the toxicity of halobenzenes. 1009 53

Rats were exposed to three levels of bromobenzene, sampled at 6, 24, and 48 h, and liver gene expression profiles were determined to identify dose and time-related changes. Expression of many genes changed transiently, and dependent on the dose. Few changes were identified after 6 h, but many genes were differentially expressed after 24 h, while after 48 h, only the high dose elicited large effects. Differentially expressed genes were involved in drug metabolism (upregulated GSTs, mEH, NQO1, Mrps, downregulated CYPs, sulfotransferases), oxidative stress (induced HO-1, peroxiredoxin, ferritin), GSH depletion (induced GCS-l, GSTA, GSTM) the acute phase response, and in processes like cholesterol, fatty acid and protein metabolism, and intracellular signaling. Trancriptional regulation via the electrophile and sterol response elements seemed to mediate part of the response to bromobenzene. Recovery of the liver was suggested in response to BB by the altered expression of genes involved in protein synthesis and cytoskeleton rearrangement. Furthermore, after 48 h, rats in the mid dose group showed no toxicity, and gene expression patterns resembled the normal situation. For certain genes (e.g., CYP4A, metallothioneins), intraday variation in expression levels was found, regardless of the treatment. Selected cDNA microarray measurements were confirmed using the specific and sensitive branched DNA signal amplification assay.
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PMID:Bromobenzene-induced hepatotoxicity at the transcriptome level. 1505

In our previous study, we demonstrated that the initial hepatic injury caused by bromobenzene (BB) was no longer detected in rats despite subsequent dosing, indicating that the liver acquired resistance to BB-induced hepatotoxicity. In this experiment, microarray analysis was conducted to characterize this resistance. The liver samples for the analysis utilized were obtained from previous experiments where F344 rats were treated intraperitoneally with BB (150 mg/kg). At 24 hr post-dose, hepatic injury was confirmed by monitoring the AST values and then the rats were maintained at the same dosing regimen for an additional 8 days. The gene expression profiles of the BB-treated rat livers were compared with a vehicle-treated group by Affymetrix RG_U34A arrays. As results, a decreased expression level of CYP3A9 and an increased expression level of GST Yc2 and glutathione peroxidase (GPX) were detected. These changes indicated suppression of the phase I reaction and induction of the phase II reaction (glutathione conjugation). Increased expression levels of epoxide hydrolase (EH) and NAD(P)H:quinone oxidoreductase (NQO1) also suggested the involvement of EH- and NQO1-mediated hydrolysis other than glutathione conjugation with resistance in the phase II reaction. Moreover, an increased expression level of abcc3 (multidrug resistance protein 3; Mrp3) was significantly noted. Based on the present findings, it was suggested that Mrp3 in the phase III reaction (drug elimination) contributed to the resistance to BB hepatotoxicity in addition to the suppression of the phase I reaction (metabolic activation) and the induction of the phase II reaction (detoxification). Among them, the factors which contributed most were considered to be the increased GST Yc2 and Mrp3, based on the degree of the gene expression changes.
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PMID:Characterization of resistance to bromobenzene-induced hepatotoxicity by microarray. 1753 37