Artigo Revisado por pares

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

2004; American Society for Pharmacology and Experimental Therapeutics; Volume: 66; Issue: 6 Linguagem: Inglês

10.1124/mol.104.004515

ISSN

1521-0111

Autores

Stephan Steckelbroeck, Yi Jin, Busola Oyesanmi, Helenius J. Kloosterboer, T.M. Penning,

Tópico(s)

Biochemical Acid Research Studies

Resumo

Tibolone is used to treat climacteric complaints and prevent osteoporosis. These beneficial effects are exerted via its 3α-and 3β-hydroxymetabolites. Undesirable stimulation of the breast and endometrium is not apparent. Endometrial stimulation is prevented by the progestogenic activity of its Δ 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 3α/3β-hydroxysteroid dehydrogenases (HSDs) on 5α-dihydrotestosterone (5α-DHT). We show that AKR1Cs also efficiently catalyze the reduction of the Δ 5(10) -3-ketosteroid tibolone to yield 3α- and 3β-hydroxytibolone. Homogeneous recombinant AKR1C1, AKR1C3, and AKR1C4 gave similar catalytic profiles to those observed with 5α-DHT. AKR1C1 catalyzed exclusively the formation of 3β-hydroxytibolone, AKR1C3 showed weak 3β/3α-HSD activity, and AKR1C4 acted predominantly as a 3α-HSD. Whereas AKR1C2 acted as a 3α-HSD toward 5α-DHT, it functioned exclusively as a 3β-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 3α-HSD with 5α-DHT to a 3β-HSD with tibolone. The preference for AKR1C1 and AKR1C2 to form 3β-hydroxytibolone, and the preference of the liver-specific AKR1C4 to form 3α-hydroxytibolone, may explain why 3β-hydroxytibolone is the major metabolite in human target tissues and why 3α-hydroxytibolone is the major circulating metabolite.

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