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Reduction and Scavenging of Chemically Reactive Drug Metabolites by NAD(P)H:Quinone Oxidoreductase 1 and NRH:Quinone Oxidoreductase 2 and Variability in Hepatic Concentrations.
Chem Res Toxicol. 2018 02 19; 31(2):116-126.CR

Abstract

Detoxicating enzymes NAD(P)H:quinone oxidoreductase 1 (NQO1) and NRH:quinone oxidoreductase 2 (NQO2) catalyze the two-electron reduction of quinone-like compounds. The protective role of the polymorphic NQO1 and NQO2 enzymes is especially of interest in the liver as the major site of drug bioactivation to chemically reactive drug metabolites. In the current study, we quantified the concentrations of NQO1 and NQO2 in 20 human liver donors and NQO1 and NQO2 activities with quinone-like drug metabolites. Hepatic NQO1 concentrations ranged from 8 to 213 nM. Using recombinant NQO1, we showed that low nM concentrations of NQO1 are sufficient to reduce synthetic amodiaquine and carbamazepine quinone-like metabolites in vitro. Hepatic NQO2 concentrations ranged from 2 to 31 μM. NQO2 catalyzed the reduction of quinone-like metabolites derived from acetaminophen, clozapine, 4'-hydroxydiclofenac, mefenamic acid, amodiaquine, and carbamazepine. The reduction of the clozapine nitrenium ion supports association studies showing that NQO2 is a genetic risk factor for clozapine-induced agranulocytosis. The 5-hydroxydiclofenac quinone imine, which was previously shown to be reduced by NQO1, was not reduced by NQO2. Tacrine was identified as a potent NQO2 inhibitor and was applied to further confirm the catalytic activity of NQO2 in these assays. While the in vivo relevance of NQO2-catalyzed reduction of quinone-like metabolites remains to be established by identification of the physiologically relevant co-substrates, our results suggest an additional protective role of the NQO2 protein by non-enzymatic scavenging of quinone-like metabolites. Hepatic NQO1 activity in detoxication of quinone-like metabolites becomes especially important when other detoxication pathways are exhausted and NQO1 levels are induced.

Authors+Show Affiliations

AIMMS-Division of Molecular Toxicology, Department of Chemistry and Pharmaceutical Sciences, Vrije Universiteit , De Boelelaan 1108, 1081 HZ Amsterdam, The Netherlands.AIMMS-Division of Molecular Toxicology, Department of Chemistry and Pharmaceutical Sciences, Vrije Universiteit , De Boelelaan 1108, 1081 HZ Amsterdam, The Netherlands.AIMMS-Division of Molecular Toxicology, Department of Chemistry and Pharmaceutical Sciences, Vrije Universiteit , De Boelelaan 1108, 1081 HZ Amsterdam, The Netherlands.AIMMS-Division of Molecular Toxicology, Department of Chemistry and Pharmaceutical Sciences, Vrije Universiteit , De Boelelaan 1108, 1081 HZ Amsterdam, The Netherlands.AIMMS-Division of Molecular Toxicology, Department of Chemistry and Pharmaceutical Sciences, Vrije Universiteit , De Boelelaan 1108, 1081 HZ Amsterdam, The Netherlands.AIMMS-Division of Molecular Toxicology, Department of Chemistry and Pharmaceutical Sciences, Vrije Universiteit , De Boelelaan 1108, 1081 HZ Amsterdam, The Netherlands.AIMMS-Division of Molecular Toxicology, Department of Chemistry and Pharmaceutical Sciences, Vrije Universiteit , De Boelelaan 1108, 1081 HZ Amsterdam, The Netherlands.AIMMS-Division of Molecular Toxicology, Department of Chemistry and Pharmaceutical Sciences, Vrije Universiteit , De Boelelaan 1108, 1081 HZ Amsterdam, The Netherlands.AIMMS-Division of Molecular Toxicology, Department of Chemistry and Pharmaceutical Sciences, Vrije Universiteit , De Boelelaan 1108, 1081 HZ Amsterdam, The Netherlands.

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

29281794

Citation

den Braver-Sewradj, Shalenie P., et al. "Reduction and Scavenging of Chemically Reactive Drug Metabolites By NAD(P)H:Quinone Oxidoreductase 1 and NRH:Quinone Oxidoreductase 2 and Variability in Hepatic Concentrations." Chemical Research in Toxicology, vol. 31, no. 2, 2018, pp. 116-126.
den Braver-Sewradj SP, den Braver MW, Toorneman RM, et al. Reduction and Scavenging of Chemically Reactive Drug Metabolites by NAD(P)H:Quinone Oxidoreductase 1 and NRH:Quinone Oxidoreductase 2 and Variability in Hepatic Concentrations. Chem Res Toxicol. 2018;31(2):116-126.
den Braver-Sewradj, S. P., den Braver, M. W., Toorneman, R. M., van Leeuwen, S., Zhang, Y., Dekker, S. J., Vermeulen, N. P. E., Commandeur, J. N. M., & Vos, J. C. (2018). Reduction and Scavenging of Chemically Reactive Drug Metabolites by NAD(P)H:Quinone Oxidoreductase 1 and NRH:Quinone Oxidoreductase 2 and Variability in Hepatic Concentrations. Chemical Research in Toxicology, 31(2), 116-126. https://doi.org/10.1021/acs.chemrestox.7b00289
den Braver-Sewradj SP, et al. Reduction and Scavenging of Chemically Reactive Drug Metabolites By NAD(P)H:Quinone Oxidoreductase 1 and NRH:Quinone Oxidoreductase 2 and Variability in Hepatic Concentrations. Chem Res Toxicol. 2018 02 19;31(2):116-126. PubMed PMID: 29281794.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Reduction and Scavenging of Chemically Reactive Drug Metabolites by NAD(P)H:Quinone Oxidoreductase 1 and NRH:Quinone Oxidoreductase 2 and Variability in Hepatic Concentrations. AU - den Braver-Sewradj,Shalenie P, AU - den Braver,Michiel W, AU - Toorneman,Robin M, AU - van Leeuwen,Stephanie, AU - Zhang,Yongjie, AU - Dekker,Stefan J, AU - Vermeulen,Nico P E, AU - Commandeur,Jan N M, AU - Vos,J Chris, Y1 - 2018/01/11/ PY - 2017/12/28/pubmed PY - 2019/4/16/medline PY - 2017/12/28/entrez SP - 116 EP - 126 JF - Chemical research in toxicology JO - Chem Res Toxicol VL - 31 IS - 2 N2 - Detoxicating enzymes NAD(P)H:quinone oxidoreductase 1 (NQO1) and NRH:quinone oxidoreductase 2 (NQO2) catalyze the two-electron reduction of quinone-like compounds. The protective role of the polymorphic NQO1 and NQO2 enzymes is especially of interest in the liver as the major site of drug bioactivation to chemically reactive drug metabolites. In the current study, we quantified the concentrations of NQO1 and NQO2 in 20 human liver donors and NQO1 and NQO2 activities with quinone-like drug metabolites. Hepatic NQO1 concentrations ranged from 8 to 213 nM. Using recombinant NQO1, we showed that low nM concentrations of NQO1 are sufficient to reduce synthetic amodiaquine and carbamazepine quinone-like metabolites in vitro. Hepatic NQO2 concentrations ranged from 2 to 31 μM. NQO2 catalyzed the reduction of quinone-like metabolites derived from acetaminophen, clozapine, 4'-hydroxydiclofenac, mefenamic acid, amodiaquine, and carbamazepine. The reduction of the clozapine nitrenium ion supports association studies showing that NQO2 is a genetic risk factor for clozapine-induced agranulocytosis. The 5-hydroxydiclofenac quinone imine, which was previously shown to be reduced by NQO1, was not reduced by NQO2. Tacrine was identified as a potent NQO2 inhibitor and was applied to further confirm the catalytic activity of NQO2 in these assays. While the in vivo relevance of NQO2-catalyzed reduction of quinone-like metabolites remains to be established by identification of the physiologically relevant co-substrates, our results suggest an additional protective role of the NQO2 protein by non-enzymatic scavenging of quinone-like metabolites. Hepatic NQO1 activity in detoxication of quinone-like metabolites becomes especially important when other detoxication pathways are exhausted and NQO1 levels are induced. SN - 1520-5010 UR - https://www.unboundmedicine.com/medline/citation/29281794/Reduction_and_Scavenging_of_Chemically_Reactive_Drug_Metabolites_by_NAD_P_H:Quinone_Oxidoreductase_1_and_NRH:Quinone_Oxidoreductase_2_and_Variability_in_Hepatic_Concentrations_ L2 - https://doi.org/10.1021/acs.chemrestox.7b00289 DB - PRIME DP - Unbound Medicine ER -