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

The characterization of the enzymatic step(s) involved in the reduction of 3'-azido-3'-deoxythymidine (zidovudine)(ZDV) to 3'-amino-3'-deoxythymidine (AMT) was pursued. AMT formation by human liver microsomes was NADPH dependent, enhanced under anaerobic conditions, and increased by flavin adenine dinucleotide (FAD) and FMN. Carbon monoxide inhibited AMT formation by up to 80%. The effect of theophylline (CYP1A substrate), tolbutamide (CYP2C substrate), chlorzoxazone, thiobenzamide, p-nitrophenol, mercaptoethanol, isoniazid (CYP2E substrates), cortisol (CYP3A substrate), ketoconazole, itraconazole, fluconazole, cimetidine, micronazole (CYP inhibitors), methimazole (flavin-containing mono-oxygenase inhibitor), chloramphenicol (undergoes nitroreduction), allopurinol (xanthine oxidase inhibitor) and dicoumarol (DT-diaphorase inhibitor) on AMT formation were studied to see if the reduction reaction was mediated by a particular isozyme. The greatest inhibition was observed with ketoconazole (concentration producing 50% inhibition = 78.0 microM). At this concentration ketoconazole acted as a non-selective inhibitor of several CYP isozymes. Overall, these data suggested that ZDV reduction was probably mediated by both cytochrome P450 isozymes and NADPH-cytochrome P450 reductase. Formation of AMT, as measured by intrinsic clearance (Clint), was significantly increased in microsomes from rats pre-treated with phenobarbitone, dexamethasone and clofibrate (inducers of CYP2B, CYP3A and CYP4A, respectively). Pre-treatment of rats with beta-naphthoflavone and ethanol (CYP1A and CYP2E1 inducers, respectively) had no effect on AMT formation.
 ...
PMID:The metabolism of zidovudine by human liver microsomes in vitro: formation of 3'-amino-3'-deoxythymidine. 805 24

To determine whether carotenoids can modulate xenobiotic-metabolizing enzymes in mice, catalytic activities of several phase I and phase II enzymes have been measured in liver microsomes and cytosol of male Swiss mice fed diets containing beta-carotene, beta-apo-8'-carotenal, canthaxanthin, or astaxanthin (300 mg/kg diet) or treated with 3-methylcholanthrene (3-MC) (3 times at 50 mg/kg ip) for 15 days. Canthaxanthin increased CYP 1A-dependent activities: ethoxyresorufin O-deethylase (EROD) was increased 3-fold, pentoxyresorufin dealkylase (PROD) was increased 2.5-fold, and methoxyresorufin O-demethylase (MROD) was increased 1.6-fold; these increases were much less than those induced by 3-MC, which induced EROD 49-fold, PROD 10-fold, and MROD 4-fold. 3-MC, but not canthaxanthin, also increased relative liver weight, liver P-450 content, NADH-cytochrome c reductase, and benzoxyresorufin dearylase. The three other carotenoids had little or no effect on phase I enzymes. Among the phase II enzyme activities, only NADPH-quinone reductase was slightly increased by 3-MC and carotenoids, except beta-carotene. Among the three carotenoids that have previously been found to be powerful CYP 1A inducers in the rat, i.e., canthaxanthin, astaxanthin, and beta-apo-8'-carotenal, only canthaxanthin shows some (weak) inducing effect of CYP 1A in the 3-MC-responsive Swiss mice, indicating that the mechanism of CYP 1A induction by carotenoids may not be the same as that by 3-MC. In addition, the fact that beta-carotene has no effect on the tested enzymes does not support the hypothesis that the modulation of xenobiotic metabolism is a possible mechanism for the antimutagenic and anticarcinogenic effects of beta-carotene, which have been demonstrated in several in vivo models in mice.
 ...
PMID:Effects of provitamin A or non-provitamin A carotenoids on liver xenobiotic-metabolizing enzymes in mice. 910 53

Four glucosinolate derivatives were evaluated individually and as a mixture for their effects on hepatic P4501A (CYP1A), glutathione S-transferase (GST), quinone reductase (QR), glutathione reductase (G-Rd), and GSH levels. Doses of the derivatives were chosen to represent their relative abundance in Brussels sprouts. Adult male F344 rats received either corn oil (vehicle); one of the agents: indole-3-carbinol (I3C, 56 mg/kg), iberin (38 mg/kg), phenylethylisothiocyanate (PEITC, 0.1 mg/kg), or cyanohydroxybutene (crambene, 50 mg/kg); or all of the agents at the doses shown (as a mixture) given by gavage daily for 7 days. The mixture and I3C caused an 11- and 9.4-fold induction of CYP1A, respectively. Crambene and I3C each caused a 1.4-fold increase in GST, while the mixture caused a 2.5-fold increase. Crambene and I3C caused a 2.5- and 1.9-fold increase in QR, respectively. The mixture caused a 6.2-fold increase. Crambene, PEITC, and the mixture caused a 1.8-, 1.6-, and 2.0-fold increase in hepatic GSH levels, respectively. Crambene, I3C, iberin, and the mixture caused 1.3-, 1.4-, 1.2-, and 1.7-fold increases in G-Rd, respectively. In a second study the mixture was given at 60 and 20% of the original dose. CYP 1A, QR, G-Rd, and GST elevations were dose-dependent; GSH levels were not elevated. It is concluded that I3C and crambene are responsible for the majority of enzyme increases seen. A synergistic effect of I3C and crambene was evident on induction of GST and QR, but not on GSH, G-Rd, or P4501A.
 ...
PMID:A comparison of the individual and collective effects of four glucosinolate breakdown products from brussels sprouts on induction of detoxification enzymes. 985 97

One of the major mechanism of chemical protection against mutagenesis, carcinogenesis and other forms of toxicity is the induction of phase-II metabolizing enzymes such as UDP-glucuronosyl transferases, glutathione S-transferases and NAD(P)H quinone reductase, or inhibition of typical phase-I reactions. The use of selective inducers of conjugating enzymes or inhibitors of CYP- and FAD-dependent monooxygenases revealed the possibility of reducing the expression of certain forms of malignancy. However, the use of some anti-initiating entities devised to reduce tumor initiation, seems to receive invalidated justification. Indeed, considering the double edge-sword nature (activating or detoxifying) of drug metabolizing enzymes as well as the myriad of xenobiotics to which human is exposed, any attempt to modulate such catalysts by dietary components (including drugs) could lead to an increased cancer risk. Paradoxically, it has been recently proposed the use of metabolizing liver preparations, isolated from phase-II induced rodents, as a novel bioactivating model in the field of genetic toxicology. Exogenous microsomal (S9) fraction prepared from 2-(3)-tert-butyl-4-hydroxyanisole (BHA) (monofunctional post-oxidative inducer) treated mice are able to increase the DNA binding and genotoxic response of pre-mutagens. On the whole, the use of enzyme modulators in cancer chemoprevention, for their ability to simultaneously reduce or increase pre-carcinogen bioactivation, should be carefully reconsidered.
 ...
PMID:The pitfall of detoxifying enzymes. 967 74

The induction of a variety of drug-metabolizing enzymes by six anthraquinones (AQs) has been investigated in the liver and small intestine of rat. In the liver, the intragastric administration for 3 days of 100 mg/kg 9,10-anthraquinone (9,10-AQ). 1-hydroxy-AQ, 1,4-dihydroxy-AQ, but not 1,2-dihydroxy-AQ and 2-carboxy-AQ, resulted in a significant induction of the UDP-GT, DT-diaphorase, P450 1A-linked monooxygenase activities and in particular the methoxyresorufin-O-demethylase (MEROD), an activity dependent on P450 1A2. Immunoblot analysis indicated that 1-hydroxy-AQ and 1,4-dihydroxy-AQ induced P450 1A2 but not 1A1 and 9,10-AQ induced both P4501A2 and P4502B. Northern blotanalysis, using a cDNA probe for CYP 1A1 and CYP 1A2, confirmed that the AQs induce CYP 1A2 but not 1A1 mRNA. In the mucosa of small intestine, none of the above-mentioned enzymatic activities were enhanced following AQ administration. The induction mechanism of the hepatic enzymes by AQs is not known and it deserves a further study as it might be independent from the activation of the Ah-receptor as reported for other tricyclic compounds. The results from inhibition experiments showed that the hydroxylated AQs were strong inhibitors of P450 1A2-dependent monooxygenases. This suggests that long-term ingestion of certain AQs, may affect the toxicity of other components present in the diet through the hepatic induction or inhibition of P450 1A2.
 ...
PMID:Heterogenous effects of anthraquinones on drug-metabolizing enzymes in the liver and small intestine of rat. 1082 54

This paper reviews studies published in the international scientific literature evaluating the influence of genetically based metabolic polymorphisms on biological indicators of genotoxic risk in environmental or occupational exposure. Exposures due to life style (i.e. diet or smoking) were not considered. Indicators are subdivided into internal dose indicators (concentration of the substance or its metabolites in biological fluids, urinary mutagenicity, adducts of hemoglobin, plasma proteins and DNA), and early biological effects (chromosome aberrations, sister chromatid exchanges, micronuclei, COMET assay, HPRT mutants). The metabolic genotypes (or phenotypes) examined by various authors are: ALDH2 (aldehyde dehydrogenase), CYP (P450 cytochrome) 1AI, CYP1A2, CYP2E1, CYP2D6, EPHX (epoxidohydrolase), NAT2 (N-acetyl transferase), NQO1 (NAD(P)H: kinone oxidoreductase), PON1 (paraoxonase), GST (glutathione S-transferase) M1, GSTT1 and GSTP1. In more than half the studies (52 out of 96), no influence of genotype was found in the biological indicator. This may be due either to the poor sensitivity of the indicator used, or to low exposure. In studies examining the effect of genotype on the indicator, the biological plausibility of the result was evaluated, i.e., whether the effect is consistent with the type of enzymatic activity expressed. Four studies reported not very reliable results and suggest either the unfavourable influence of genotype GSTM1 with high detoxifying activity, or enzymatic activity poorly involved in the metabolism of the xenobiotics in question (NAT2 in the case of PAH). As regards urinary metabolites of genotoxic agents, eight studies reported the modulating effect of genotype. The urinary excretion of mercapturic acids was greater in subjects with high GST activity. In exposure to PAH, urinary 1-pyrenol and PAH metabolites turn out to be significantly influenced by genotypes CYP1A1 or GSTM1 null; in exposure to aromatic amines, the influence of NAT2 on exposure indicators (levels of acetylated and non-acetylated metabolites) was confirmed. Exposure to benzene led to an increase in t-t-MA in some genotypes, although experimental verification is still necessary. As regards urinary mutagenicity, the effect of genotype GSTM1 null is reported, and of the same genotype combined with NAT2 slow, in non-smoking individuals subjected to high exposure to PAH and in cigarette-smoking/coke-oven workers. Lastly, the determination of urinary metabolites in monitoring exposure to genotoxic substances, provides sufficient evidence that genetically based metabolic polymorphisms must be taken into account in the future. There is still little evidence regarding the importance of genotype on the level of protein adducts in environmental and occupational exposure. A relatively large number of publications (22) dealt with DNA adduct levels in PAH exposure. In 18 studies, the biological indicator clearly increases with respect to values in control subjects. Of these studies, seven reported the influence of GSTM1 null on DNA adducts and, of the five studies which also examined genotype CYP1A1, four reported the influence on DNA adduct level of genotype CYP1A1, alone or in combination with GSTM1 null. It therefore seems as if the unfavourable association for the activating/detoxifying metabolism of PAH is a risk factor for the formation of PAH-DNA adducts. Most publications (25 out of 41; 61%) dealing with metabolic polymorphisms in effect indicators (cytogenetic markers, COMET assay, HPRT mutants) did not report any increase in the indicator due to exposure to the genotoxic agents studied. These indicators of genotoxic damage, including mainly the frequency of HPRT mutants (100%), Mn (90%) and the COMET assay (67%), are not sufficiently sensitive in revealing exposure, confirming that they are not particularly suitable for measuring exposure to genotoxic substances in occupational or environmental exposures. It is therefore difficult to assess the influence of metabolic genotypes by means of this type of biological indicator. The few positive results reported for SCE in occupational studies mentioned the influence of genotype ALDH2, either alone or in combination with genotype CYP2E1 in exposure to CVM, or in combination with GSTM1 null in exposure to epichlorohydrin. For CA the results showed unfavourable combinations of genotypes CYP2E1, GSTM1 and PON1 in exposure to pesticides, and GSTM1 null in combination with NAT2 slow in exposure to urban air. All the remaining studies on the effect of genotype on biological indicators of cytogenetic damage reported negative results.
 ...
PMID:[Biomarkers of gentotoxic risk and metabolic polymorphism]. 1118 84

Environmental pollutants, such as polychlorinated biphenyls (PCBs), may induce drug metabolism and may be substrates for the induced metabolic enzymes. Both processes may lead to oxidative stress. The goal of this study was to determine the influence of polychlorinated biphenyls, selected as inducers and substrates of drug metabolism, on oxidative events within the liver over a 3-week time course. Male and female Sprague-Dawley rats received two ip injections per week of 4-chlorobiphenyl, 2,4,4'-trichlorobiphenyl, 3,4,5-trichlorobiphenyl, 3,3',4,4'-tetrachlorobiphenyl (PCB 77), 2,2',4,4',5,5'-hexachlorobiphenyl (PCB 153), or both PCB 77 and 153 (100 micromol/kg/injection) and were euthanized at the end of 1, 2, or 3 weeks. Hepatic cytochrome P450 1A1 (EROD) activity, DT-diaphorase activity, AP-1 DNA-binding activity, conjugated dienes, and alpha-tocopherol (vitamin E) as well as alpha-tocopheryl quinone (oxidized vitamin E) were determined. While the lower chlorinated biphenyls (at these doses and times) showed little or no effect on these oxidative stress parameters, both CYP 1A1 and DT-diaphorase activities were significantly increased in both male and female rats receiving PCB 77, a ligand for the aryl hydrocarbon receptor. In addition, the DNA-binding activity of the transcription factor AP-1 was increased in rats treated with PCB 77 or PCB 153. Within the lipid fraction there was no significant increase observed in conjugated diene concentrations, but there was a significant increase in alpha-tocopheryl quinone upon treatment with all PCBs tested. These data indicate that alpha-tocopheryl quinone may be a sensitive marker for PCB exposure and is possibly increased by a wide range of PCBs.
 ...
PMID:Polychlorinated biphenyl-induced effects on metabolic enzymes, AP-1 binding, vitamin E, and oxidative stress in the rat liver. 1122 84

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.
 ...
PMID:Induction by xenobiotics of phase I and phase II enzyme activities in the human keratinocyte cell line NCTC 2544. 1169 72

1. Addition of Cr VI (dichromate) to isolated rat hepatocytes results in rapid glutathione oxidation, reactive oxygen species (ROS) formation, lipid peroxidation, decreased mitochondrial membrane potential and lysosomal membrane rupture before hepatocyte lysis occurred. 2. Cytotoxicity was prevented by "ROS" scavengers, antioxidants, and glutamine (ATP generator). Hepatocyte dichlorofluorescin oxidation (to determine ROS/Cr V formation) was inhibited by mannitol (a hydroxyl radical scavenger) or butylated hydroxyanisole and butylated hydroxytoluene (antioxidants). 3. The Cr VI reductive mechanism required for toxicity are not known. Cytotoxicity was also prevented by cytochrome P450 inhibitors, particularly CYP 2E1 inhibitors, but not inhibitors of DT diaphorase or glutathione reductase. This suggests that P450 reductase and/or reduced cytochrome P450 contributes to Cr VI reduction to Cr IV. 4. Glutathione depleted hepatocytes were resistant to Cr (VI) toxicity and much less dichlorofluorescin oxidation occurred. Reduction of dichromate by glutathione or cysteine in vitro was also accompanied by oxygen uptake and was inhibited by Mn II (a Cr IV reductant ). Cr VI induced cytotoxicity and ROS formation was also inhibited by Mn II which suggests that Cr IV and Cr IV.GSH mediate "ROS" formation in isolated hepatocytes. 5. In conclusion Cr VI cytotoxicity is associated with mitochondrial/lysosomal toxicity by the biological reactive intermediates Cr IV and "ROS".
 ...
PMID:Biological reactive intermediates that mediate chromium (VI) toxicity. 1176 36

Naturally occurring phenolics, protocatechuic and tannic acids have been reported to be inhibitors of chemical mutagenesis and carcinogenesis in experimental models. Here, we have studied the effect of pretreatment with these compounds on MC-induced cytochrome P450 and phase II enzymes in rats. The male Wistar rats were treated intraperitoneally with protocatechuic acid and tannic acid in the dose of 50mg/kg every 3 days for 2 weeks. MC was administered at the 12th day of phenolics treatment. The activities of EROD (CYP1A1), MROD (CYP1A2), PROD (CYP2B), PNPH (CYP2E1), GST, UDPGT, NQO1 were measured in the liver and kidney. Protocatechuic acid treatment minimally reduced the MC-induced EROD and MROD, but the observed differences were statistically significant. This compound was also a weak inhibitor of hepatic PNPH. Moreover, Western blot analysis with CYP1A1/1A2- and CYP2E1-specific antibodies showed the same effect in the levels of hepatic CYP1A1/1A2 and CYP2E1. Minimal decrease of renal constitutive (by 23%) and more significant reduction of induced form (by 66%) of PNPH was found as result of treatment with protocatechuic acid. Tannic acid alone had no effect on cytochrome P450 enzymes while in combination with MC this polyphenol minimally enhanced the MC induction of MROD and in greater extent PNPH in liver. The treatment with protocatechuic acid alone enhanced slightly the activities of all three phase II enzymes in liver. The pretreatment with this phenolic of the MC-induced rats however significantly increased the activities of hepatic GST and NQO1 in comparison with MC-treated group. In kidney MC-induced activity of NQO1 was reduced (about 43%) to the control level by tannic acid pretreatment. The results of our present study indicate that in rat the prolonged treatment with protocatechuic acid affects differently the activities of CYP and phase II enzyme when compared to tannic acid. Moreover, the effect of this polyphenols significantly depends on the method of treatment.
 ...
PMID:Modulation of 3-methylcholanthrene-induced rat hepatic and renal cytochrome P450 and phase II enzymes by plant phenols: protocatechuic and tannic acids. 1530 93


1 2 3 Next >>