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Research ArticleArticle

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

Arne Meyer, Anna Vuorinen, Agnieszka E. Zielinska, Petra Strajhar, Gareth G. Lavery, Daniela Schuster and Alex Odermatt
Drug Metabolism and Disposition September 2013, 41 (9) 1671-1678; DOI: https://doi.org/10.1124/dmd.113.052936
Arne Meyer
Swiss Center for Applied Human Toxicology and Division of Molecular and Systems Toxicology, Department of Pharmaceutical Sciences, University of Basel, Basel, Switzerland (A.M., P.S., A.O.); Institute of Pharmacy/Pharmaceutical Chemistry and Center for Molecular Biosciences Innsbruck, University of Innsbruck, Innsbruck, Austria (A.V., D.S.); and Centre for Endocrinology Diabetes and Metabolism, Institute of Biomedical Research, School of Clinical and Experimental Medicine, College of Medical and Dental Sciences, University of Birmingham, Birmingham, United Kingdom (A.E.Z., G.G.L.)
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Anna Vuorinen
Swiss Center for Applied Human Toxicology and Division of Molecular and Systems Toxicology, Department of Pharmaceutical Sciences, University of Basel, Basel, Switzerland (A.M., P.S., A.O.); Institute of Pharmacy/Pharmaceutical Chemistry and Center for Molecular Biosciences Innsbruck, University of Innsbruck, Innsbruck, Austria (A.V., D.S.); and Centre for Endocrinology Diabetes and Metabolism, Institute of Biomedical Research, School of Clinical and Experimental Medicine, College of Medical and Dental Sciences, University of Birmingham, Birmingham, United Kingdom (A.E.Z., G.G.L.)
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Agnieszka E. Zielinska
Swiss Center for Applied Human Toxicology and Division of Molecular and Systems Toxicology, Department of Pharmaceutical Sciences, University of Basel, Basel, Switzerland (A.M., P.S., A.O.); Institute of Pharmacy/Pharmaceutical Chemistry and Center for Molecular Biosciences Innsbruck, University of Innsbruck, Innsbruck, Austria (A.V., D.S.); and Centre for Endocrinology Diabetes and Metabolism, Institute of Biomedical Research, School of Clinical and Experimental Medicine, College of Medical and Dental Sciences, University of Birmingham, Birmingham, United Kingdom (A.E.Z., G.G.L.)
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Petra Strajhar
Swiss Center for Applied Human Toxicology and Division of Molecular and Systems Toxicology, Department of Pharmaceutical Sciences, University of Basel, Basel, Switzerland (A.M., P.S., A.O.); Institute of Pharmacy/Pharmaceutical Chemistry and Center for Molecular Biosciences Innsbruck, University of Innsbruck, Innsbruck, Austria (A.V., D.S.); and Centre for Endocrinology Diabetes and Metabolism, Institute of Biomedical Research, School of Clinical and Experimental Medicine, College of Medical and Dental Sciences, University of Birmingham, Birmingham, United Kingdom (A.E.Z., G.G.L.)
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Gareth G. Lavery
Swiss Center for Applied Human Toxicology and Division of Molecular and Systems Toxicology, Department of Pharmaceutical Sciences, University of Basel, Basel, Switzerland (A.M., P.S., A.O.); Institute of Pharmacy/Pharmaceutical Chemistry and Center for Molecular Biosciences Innsbruck, University of Innsbruck, Innsbruck, Austria (A.V., D.S.); and Centre for Endocrinology Diabetes and Metabolism, Institute of Biomedical Research, School of Clinical and Experimental Medicine, College of Medical and Dental Sciences, University of Birmingham, Birmingham, United Kingdom (A.E.Z., G.G.L.)
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Daniela Schuster
Swiss Center for Applied Human Toxicology and Division of Molecular and Systems Toxicology, Department of Pharmaceutical Sciences, University of Basel, Basel, Switzerland (A.M., P.S., A.O.); Institute of Pharmacy/Pharmaceutical Chemistry and Center for Molecular Biosciences Innsbruck, University of Innsbruck, Innsbruck, Austria (A.V., D.S.); and Centre for Endocrinology Diabetes and Metabolism, Institute of Biomedical Research, School of Clinical and Experimental Medicine, College of Medical and Dental Sciences, University of Birmingham, Birmingham, United Kingdom (A.E.Z., G.G.L.)
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Alex Odermatt
Swiss Center for Applied Human Toxicology and Division of Molecular and Systems Toxicology, Department of Pharmaceutical Sciences, University of Basel, Basel, Switzerland (A.M., P.S., A.O.); Institute of Pharmacy/Pharmaceutical Chemistry and Center for Molecular Biosciences Innsbruck, University of Innsbruck, Innsbruck, Austria (A.V., D.S.); and Centre for Endocrinology Diabetes and Metabolism, Institute of Biomedical Research, School of Clinical and Experimental Medicine, College of Medical and Dental Sciences, University of Birmingham, Birmingham, United Kingdom (A.E.Z., G.G.L.)
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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.

Footnotes

    • Received May 13, 2013.
    • Accepted June 26, 2013.
  • This work was supported by the Swiss National Science Foundation [Grant PDFMP3-127330] (to A.O.); and a BBSRC David Philips fellowship [Grant BB/G023468/1] (to G.L.).

  • A.O. has a Chair for Molecular and Systems Toxicology by the Novartis Research Foundation. A.V. is supported by a Ph.D. grant from the Austrian Academy of Sciences and has received financial support from the University of Innsbruck’s Young Talents Grants (Nachwuchsförderung). D.S. is financed by the Erika Cremer Habilitation Program of the University of Innsbruck.

  • dx.doi.org/10.1124/dmd.113.052936.

  • Copyright © 2013 by The American Society for Pharmacology and Experimental Therapeutics
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Drug Metabolism and Disposition: 41 (9)
Drug Metabolism and Disposition
Vol. 41, Issue 9
1 Sep 2013
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Research ArticleArticle

Carbonyl Reduction of Bupropion by 11β-HSD1

Arne Meyer, Anna Vuorinen, Agnieszka E. Zielinska, Petra Strajhar, Gareth G. Lavery, Daniela Schuster and Alex Odermatt
Drug Metabolism and Disposition September 1, 2013, 41 (9) 1671-1678; DOI: https://doi.org/10.1124/dmd.113.052936

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Research ArticleArticle

Carbonyl Reduction of Bupropion by 11β-HSD1

Arne Meyer, Anna Vuorinen, Agnieszka E. Zielinska, Petra Strajhar, Gareth G. Lavery, Daniela Schuster and Alex Odermatt
Drug Metabolism and Disposition September 1, 2013, 41 (9) 1671-1678; DOI: https://doi.org/10.1124/dmd.113.052936
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