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Tibolone Is Metabolized by the 3/3-Hydroxysteroid Dehydrogenase Activities of the Four Human Isozymes of the Aldo-Keto Reductase 1C Subfamily: Inversion of Stereospecificity with a ⁵⁽¹⁰⁾-3-Ketosteroid

Department of Pharmacology, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania (S.S., Y.J., B.O., T.M.P.); and Research and Development Laboratories, N.V. Organon, Oss, The Netherlands (H.J.K.)

Tibolone is used to treat climacteric complaints and prevent osteoporosis. These beneficial effects are exerted via its 3-and 3-hydroxymetabolites. Undesirable stimulation of the breast and endometrium is not apparent. Endometrial stimulation is prevented by the progestogenic activity of its ⁴-ene metabolite. The enzymes responsible for the formation of these active metabolites are unknown. Human aldo-keto reductase (AKR)1C isoforms have been shown to act as 3/3-hydroxysteroid dehydrogenases (HSDs) on 5-dihydrotestosterone (5-DHT). We show that AKR1Cs also efficiently catalyze the reduction of the ⁵⁽¹⁰⁾-3-ketosteroid tibolone to yield 3- and 3-hydroxytibolone. Homogeneous recombinant AKR1C1, AKR1C3, and AKR1C4 gave similar catalytic profiles to those observed with 5-DHT. AKR1C1 catalyzed exclusively the formation of 3-hydroxytibolone, AKR1C3 showed weak 3/3-HSD activity, and AKR1C4 acted predominantly as a 3-HSD. Whereas AKR1C2 acted as a 3-HSD toward 5-DHT, it functioned exclusively as a 3-HSD on tibolone. Furthermore, strong substrate inhibition was observed for the AKR1C2 catalyzed reduction of tibolone. Using NAD⁺, the 3-hydroxymetabolites were efficiently oxidized by homogeneous recombinant AKR1C2 and AKR1C4. However, because of potent inhibition of this activity by NADPH, AKR1Cs will probably act only as 3-ketosteroid reductases in vivo. Molecular docking simulations using crystal structures of AKR1C1 and AKR1C2 explained why AKR1C2 inverted its stereospecificity from a 3-HSD with 5-DHT to a 3-HSD with tibolone. The preference for AKR1C1 and AKR1C2 to form 3-hydroxytibolone, and the preference of the liver-specific AKR1C4 to form 3-hydroxytibolone, may explain why 3-hydroxytibolone is the major metabolite in human target tissues and why 3-hydroxytibolone is the major circulating metabolite.

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