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  • Progestins as inhibitors of the human 20-ketosteroid reductases, AKR1C1 and AKR1C3
    Beranič, Nataša, 1985- ; Gobec, Stanislav, 1970- ; Lanišnik-Rižner, Tea
    The human aldo-keto reductases 1C1 and 1C3 (AKR1C1 and AKR1C3) are important 20-ketosteroid reductases in pre-receptor regulation of progesterone action. Both AKR1C1 and AKR1C3 convert progesterone ... to the less potent metabolite 20alpha-hydroxyprogesterone, although AKR1C1 has a higher catalytic efficiencythan AKR1C3. Recently, we reported significant up-regulation of AKR1C1 and AKR1C3 in ovarian endometriosis, a complex estrogen-dependent disease. The typical characteristics of endometriosis are increased formation of estradiol, which stimulates proliferation of endometriotic tissue, and disturbed action of the protective progesterone. Although progestins have beenused for treatment of endometriosis since the 1960s, their detailed mechanisms of action are still not completely understood. In the present study, we evaluated the potential inhibitory effects of progestins on the pre-receptor regulatory enzymes AKR1C1 and AKR1C3. We examined the following progestins as inhibitors of progesterone reduction catalyzed by recombinant AKR1C1 and AKR1C3: progesterone derivatives (dydrogesterone, its metabolite, 20alpha-hydroxydydrogesterone; and medroxyprogesterone acetate), 19-nortestosterone derivatives (desogestrel, norethinodrone and levonorgestrel), and the androgen danazol. Dydrogesterone, medroxyprogesteroneacetate, 20alpha-hydroxydydrogesterone and norethinodrone inhibited AKR1C1 and AKR1C3 with Ki values of 1.9microM, 7.9microM, 20.8microMand 48.0microM, and of 0.5microM, 1.4microM, 18.6microM and 6.6microM, respectively. Levonorgestrel and desogestrel preferentially inhibited AKR1C3 with Ki values of 5.6microM and 39.1microM, respectively. -hydroxydOurdata thus show that dydrogesterone, medroxyprogesterone acetate, 20
    Vir: Enzymology and molecular biology of carbonyl metabolism (Str. 227-233)
    Vrsta gradiva - prispevek na konferenci
    Leto - 2011
    Jezik - angleški
    COBISS.SI-ID - 27778009
    DOI

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