Molnari Jillissa C, Myers Alan L
Department of Pharmaceutical, Biomedical and Administrative Sciences, College of Pharmacy and Health Sciences, Drake University, Des Moines, IA, USA.
Xenobiotica. 2012 Jun;42(6):550-61. doi: 10.3109/00498254.2011.643416. Epub 2012 Feb 20.
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 carbonyl reducing enzymes in hepatic microsomes are significant players in bupropion reduction. Contrary to past studies, we found that threohydrobupropion (not hydroxybupropion) is the major microsomal generated hepatic metabolite of bupropion.
安非他酮在人体内通过氧化和还原过程被广泛代谢。细胞色素P450 2B6（CYP2B6）介导安非他酮氧化为羟基安非他酮，但催化安非他酮在人肝脏中羰基还原为赤藓型和苏阿糖型羟基安非他酮的酶尚不清楚。本研究的目的是研究人肝脏中安非他酮还原的酶动力学。在人肝脏胞质溶胶中，安非他酮还原为赤藓型和苏阿糖型羟基安非他酮依赖于烟酰胺腺嘌呤二核苷酸磷酸（NADPH），内在清除率（Cl(int)）值分别为0.08和0.60μL·min⁻¹mg⁻¹蛋白质。肝脏微粒体中安非他酮的还原也依赖于NADPH，Cl(int)值分别为10.4和280μL·min⁻¹mg⁻¹蛋白质。微粒体中赤藓型和苏阿糖型羟基安非他酮的生成量分别比胞质溶胶中的高出70倍和170倍。甲萘醌是一种胞质羰基还原酶（如羰基还原酶（CBRs））的抑制剂，分别以30和54μM的半数抑制浓度（IC(50)）抑制胞质溶胶中赤藓型和苏阿糖型羟基安非他酮的生成。在微粒体中，18β-甘草次酸是微粒体羰基还原酶（如11β-羟基类固醇脱氢酶（11β-HSDs））的抑制剂，分别以25和26 nM的IC(50)抑制它们的生成。我们的研究结果与最近关于人胎盘的研究一致，表明肝脏微粒体中的羰基还原酶在安非他酮还原中起重要作用。与过去的研究相反，我们发现苏阿糖型羟基安非他酮（而非羟基安非他酮）是微粒体生成的安非他酮的主要肝脏代谢产物。
