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)

Genetic polymorphisms in xenobiotic metabolizing enzymes can have profound influence on enzyme function, with implications for chemical clearance and internal dose. The effects of polymorphisms have been evaluated for certain therapeutic drugs but there has been relatively little investigation with environmental toxicants. Polymorphisms can also affect the function of host defense mechanisms and thus modify the pharmacodynamic response. This review and analysis explores the feasibility of using polymorphism data in human health risk assessment for four enzymes, two involved in conjugation (uridine diphosphoglucuronosyltransferases [UGTs], sulfotransferases [SULTs]), and two involved in detoxification (microsomal epoxide hydrolase [EPHX1], NADPH quinone oxidoreductase I [NQO1]). This set of evaluations complements our previous analyses with oxidative and conjugating enzymes. Of the numerous UGT and SULT enzymes, the greatest likelihood for polymorphism effect on conjugation function are for SULT1A1 (*2 polymorphism), UGT1A1 (*6, *7, *28 polymorphisms), UGT1A7 (*3 polymorphism), UGT2B15 (*2 polymorphism), and UGT2B17 (null polymorphism). The null polymorphism in NQO1 has the potential to impair host defense. These highlighted polymorphisms are of sufficient frequency to be prioritized for consideration in chemical risk assessments. In contrast, SNPs in EPHX1 are not sufficiently influential or defined for inclusion in risk models. The current analysis is an important first step in bringing the highlighted polymorphisms into a physiologically based pharmacokinetic (PBPK) modeling framework.
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PMID:Genetic polymorphism in metabolism and host defense enzymes: implications for human health risk assessment. 2066 11

The present work reports data regarding effects of an induced oxidative stress on the mainly expressed isoforms of UDP-glucuronosyltransferases (UGTs) in the brain. UGT1A6 and UGT1A7 expression and enzymatic activities toward the 1-naphthol were analyzed in rat cultured astrocytes following the exposure for 48 h to redox-cycling xenobiotic compounds such as quinones and bipyridinium ions. The expression of NADPH:cytochrome P450 reductase and NAD(P)H:quinone oxidoreductase 1 (NQO1) was also investigated. Oxidative stress induced significant deleterious changes in astrocyte morphology, decreased cell viability and inhibited catalytic function of UGTs as a result of protein oxidation. Alternatively, in the surviving impaired astrocytes, oxidative conditions induced a significant overactivity and overexpression of xenobiotic detoxification enzymes, as adaptive response. These effects were significantly prevented by the presence of melatonin, suggesting its direct antioxidant action on reactive oxygen species, reflected further on the glucuronidation activity and transcriptional regulation of both UGT1A6 and UGT1A7. Results show that both catalytic properties of UGTs and the expression of UGT1A6, UGT1A7, NQO1 and NADPH:cytochrome P450 reductase in rat astrocytes are greatly influenced by the pro-oxidative environment. In conclusion, an experimental increase in oxidative cellular status could have both immediate and long term consequences on detoxification enzymatic system activity and expression.
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PMID:Effect of oxidative stress on UDP-glucuronosyltransferases in rat astrocytes. 2284 77

Tanshinone I (TSI) is a lipophilic diterpene in Salvia miltiorrhiza with versatile pharmacological activities. However, metabolic pathway of TSI in human is unknown. In this study, we determined major metabolites of TSI using a preparation of human liver microsomes (HLMs) by HPLC-UV and Q-Trap mass spectrometer. A total of 6 metabolites were detected, which indicated the presence of hydroxylation, reduction as well as glucuronidation. Selective chemical inhibition and purified cytochrome P450 (CYP450) isoform screening experiments revealed that CYP2A6 was primarily responsible for TSI Phase I metabolism. Part of generated hydroxylated TSI was glucuronidated via several glucuronosyltransferase (UGT) isoforms including UGT1A1, UGT1A3, UGT1A7, UGT1A9, as well as extrahepatic expressed isoforms UGT1A8 and UGT1A10. TSI could be reduced to a relatively unstable hydroquinone intermediate by NAD(P)H: quinone oxidoreductase 1 (NQO1), and then immediately conjugated with glucuronic acid by a panel of UGTs, especially UGT1A9, UGT1A1 and UGT1A8. Additionally, NQO1 could also reduce hydroxylated TSI to a hydroquinone intermediate, which was immediately glucuronidated by UGT1A1. The study demonstrated that hydroxylation, reduction as well as glucuronidation were the major pathways for TSI biotransformation, and six metabolites generated by CYPs, NQO1 and UGTs were found in HLMs and S9 subcellular fractions.
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PMID:Metabolic characteristics of Tanshinone I in human liver microsomes and S9 subcellular fractions. 2935 26