Swiss Center for Applied Human Toxicology and Division of Molecular and Systems Toxicology, Department of Pharmaceutical Sciences, University of Basel, Basel, Switzerland.
Drug Metab Dispos. 2013 Sep;41(9):1671-8. doi: 10.1124/dmd.113.052936. Epub 2013 Jun 26.
Bupropion is widely used for treatment of depression and as a smoking-cessation drug. Despite more than 20 years of therapeutic use, its metabolism is not fully understood. While CYP2B6 is known to form hydroxybupropion, the enzyme(s) generating erythro- and threohydrobupropion have long remained unclear. Previous experiments using microsomal preparations and the nonspecific inhibitor glycyrrhetinic acid suggested a role for 11β-hydroxysteroid dehydrogenase 1 (11β-HSD1) in the formation of both erythro- and threohydrobupropion. 11β-HSD1 catalyzes the conversion of inactive glucocorticoids (cortisone, prednisone) to their active forms (cortisol, prednisolone). Moreover, it accepts several other substrates. Here, we used for the first time recombinant 11β-HSD1 to assess its role in the carbonyl reduction of bupropion. Furthermore, we applied human, rat, and mouse liver microsomes and a selective inhibitor to characterize species-specific differences and to estimate the relative contribution of 11β-HSD1 to bupropion metabolism. The results revealed 11β-HSD1 as the major enzyme responsible for threohydrobupropion formation. The reaction was stereoselective and no erythrohydrobupropion was formed. Human liver microsomes showed 10 and 80 times higher activity than rat and mouse liver microsomes, respectively. The formation of erythrohydrobupropion was not altered in experiments with microsomes from 11β-HSD1-deficient mice or upon incubation with 11β-HSD1 inhibitor, indicating the existence of another carbonyl reductase that generates erythrohydrobupropion. Molecular docking supported the experimental findings and suggested that 11β-HSD1 selectively converts R-bupropion to threohydrobupropion. Enzyme inhibition experiments suggested that exposure to bupropion is not likely to impair 11β-HSD1-dependent glucocorticoid activation but that pharmacological administration of cortisone or prednisone may inhibit 11β-HSD1-dependent bupropion metabolism.
安非他酮被广泛用于治疗抑郁症和戒烟。尽管已经使用了 20 多年，但它的代谢机制仍不完全清楚。虽然 CYP2B6 已知能形成羟基安非他酮，但产生赤型和苏型安非他酮的酶一直不清楚。以前使用微粒体制剂和非特异性抑制剂甘草酸的实验表明，11β-羟甾类脱氢酶 1（11β-HSD1）在形成赤型和苏型安非他酮中起作用。11β-HSD1 催化将无活性的糖皮质激素（可的松、泼尼松）转化为其活性形式（皮质醇、泼尼松龙）。此外，它还接受其他几种底物。在这里，我们首次使用重组 11β-HSD1 来评估其在安非他酮羰基还原中的作用。此外，我们应用人、大鼠和小鼠肝微粒体和选择性抑制剂来描述种属特异性差异，并估计 11β-HSD1 对安非他酮代谢的相对贡献。结果表明，11β-HSD1 是产生苏型安非他酮的主要酶。该反应具有立体选择性，没有形成赤型安非他酮。人肝微粒体的活性比大鼠和小鼠肝微粒体分别高 10 倍和 80 倍。在缺乏 11β-HSD1 的小鼠肝微粒体或用 11β-HSD1 抑制剂孵育的实验中，赤型安非他酮的形成没有改变，这表明存在另一种产生赤型安非他酮的羰基还原酶。分子对接支持了实验结果，并表明 11β-HSD1 选择性地将 R-安非他酮转化为苏型安非他酮。酶抑制实验表明，暴露于安非他酮不太可能损害 11β-HSD1 依赖性糖皮质激素激活，但皮质醇或泼尼松龙的药理学给药可能抑制 11β-HSD1 依赖性安非他酮代谢。
