Carbonyl reduction of bupropion in human liver

Xenobiotica; the Fate of Foreign Compounds in Biological Systems
Jillissa C Molnari, Alan L Myers

Abstract

Bupropion is metabolized extensively in humans by oxidative and reductive processes. CYP2B6 mediates oxidation of bupropion to hydroxybupropion, but the enzyme(s) catalyzing carbonyl reduction of bupropion to erythro- and threohydrobupropion in human liver is unknown. The objective of this study was to examine the enzyme kinetics of bupropion reduction in human liver. In human liver cytosol, the reduction of bupropion to erythro-and threohydrobupropion was NADPH dependent with Cl(int) values of 0.08 and 0.60 µL·min(-1)mg(-1) protein, respectively. Bupropion reduction in liver microsomes was also NADPH dependent with Cl(int) values of 10.4 and 280 µL·min(-1)mg(-1) protein, respectively. Formation of erythro-and threohydrobupropion in microsomes exceeded that in cytosol by 70 and 170 fold, respectively. Menadione, an inhibitor of cytosolic carbonyl reducing enzymes (e.g. CBRs), inhibited erythro-and threohydrobupropion formation in cytosol with IC(50) of 30 and 54 µM, respectively. In microsomes 18β-glycyrrhetinic acid, an inhibitor of microsomal carbonyl reductases (e.g. 11β-HSDs), inhibited their formation with IC(50) of 25 and 26 nM, respectively. Our findings, in agreement with recent human placental studies, show that carbon...Continue Reading

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Citations

Jun 28, 2013·Drug Metabolism and Disposition : the Biological Fate of Chemicals·Arne MeyerAlex Odermatt
Sep 30, 2015·Drug Metabolism Reviews·Iva BoušováPetra Matoušková
Nov 1, 2013·Drug Metabolism Reviews·Petra Malátková, Vladimír Wsól
Jan 24, 2016·Drug Metabolism and Disposition : the Biological Fate of Chemicals·Brandon T GuffordZeruesenay Desta
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Oct 21, 2016·Drug Metabolism and Disposition : the Biological Fate of Chemicals·Valentina M FokinaTatiana N Nanovskaya
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Jul 18, 2017·Expert Opinion on Drug Metabolism & Toxicology·Sophia M Shi, Li Di
Jul 25, 2017·Xenobiotica; the Fate of Foreign Compounds in Biological Systems·Raghava Choudary PalacharlaIlayaraja Kalaikadhiban
Sep 7, 2017·Xenobiotica; the Fate of Foreign Compounds in Biological Systems·Ranjeet Prasad DashNuggehally R Srinivas
Apr 21, 2018·Drug Metabolism and Disposition : the Biological Fate of Chemicals·Xin YangLi Di
Apr 24, 2015·Drug Metabolism and Disposition : the Biological Fate of Chemicals·Jamie N ConnarnDuxin Sun
Oct 22, 2014·Drug Metabolism and Disposition : the Biological Fate of Chemicals·Osama Y AlshogranThomas D Nolin
Jul 11, 2020·Clinical Pharmacology in Drug Development·Mohamed-Eslam F MohamedAhmed A Othman

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