Formation of Threohydrobupropion from Bupropion Is Dependent on 11b-Hydroxysteroid Dehydrogenase 1

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 erythroand threohydrobupropion have long remained unclear. Previous experiments using microsomal preparations and the nonspecific inhibitor glycyrrhetinic acid suggested a role for 11b-hydroxysteroid dehydrogenase 1 (11b-HSD1) in the formation of both erythroand threohydrobupropion. 11b-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 11b-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 11b-HSD1 to bupropion metabolism. The results revealed 11b-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 11b-HSD1-deficient mice or upon incubation with 11b-HSD1 inhibitor, indicating the existence of another carbonyl reductase that generates erythrohydrobupropion. Molecular docking supported the experimental findings and suggested that 11b-HSD1 selectively converts R-bupropion to threohydrobupropion. Enzyme inhibition experiments suggested that exposure to bupropion is not likely to impair 11b-HSD1-dependent glucocorticoid activation but that pharmacological administration of cortisone or prednisone may inhibit 11b-HSD1-dependent bupropion