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Formation of threohydrobupropion from bupropion is dependent on 11β-hydroxysteroid dehydrogenase 1.
Formation of threohydrobupropion from bupropion is dependent on 11β-hydroxysteroid dehydrogenase 1.
- Source :
-
Drug metabolism and disposition: the biological fate of chemicals [Drug Metab Dispos] 2013 Sep; Vol. 41 (9), pp. 1671-8. Date of Electronic Publication: 2013 Jun 26. - Publication Year :
- 2013
-
Abstract
- 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.
- Subjects :
- Aged
Animals
Bupropion pharmacokinetics
Cell Line
Cortisone metabolism
HEK293 Cells
Humans
Male
Mice
Mice, Inbred C57BL
Mice, Knockout
Microsomes, Liver enzymology
Microsomes, Liver metabolism
Oxidation-Reduction
Prednisone pharmacokinetics
Rats
Rats, Sprague-Dawley
11-beta-Hydroxysteroid Dehydrogenase Type 1 metabolism
Bupropion analogs & derivatives
Bupropion metabolism
Subjects
Details
- Language :
- English
- ISSN :
- 1521-009X
- Volume :
- 41
- Issue :
- 9
- Database :
- MEDLINE
- Journal :
- Drug metabolism and disposition: the biological fate of chemicals
- Publication Type :
- Academic Journal
- Accession number :
- 23804523
- Full Text :
- https://doi.org/10.1124/dmd.113.052936