19-Nortestosterone系Progestinの代謝と生物学的活性
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概要
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Recently, many synthetic steroids were reported to be effective as progestational agents. Among these, 17α-methyl-19nortestosterone and 17α-ethynyl-19nortestosterone were the most useful agents for clinnical use. These two steroids, however, showed no progestational effects when they were directly applied in the uterus. And, in addition, apart from the progestational activity, these steroids have been proved to show androgenic and estrogenic activities. Although the effects of these steroids were suggested to be derived from the-metabolites generated in vivo, the metabolism of these steroids was yet unknown. In this experiment, metabolism of these steroids was studied in vivo and in vitro.<BR>The 17α-methyl-19-nortestosterone and 17α-ethynyl-19-nortestostterone were labelled with tritium according to Wilzbach's method.<BR>The labelled 17α-methyl-19-nortestosterone was incubated in vitro with female rat liver homogenate under aerobic conditions. Reduction of ring A was suggested by the decrease of UV absorbing material in the reaction mixture, and the reaction was strongly accelerated by the addition of NADPH in the incubation medium. The extract was chromatographied on paper, and two radioactive metabolites were separated on the paper chromatograph. One was compared with authentic 17α-methyl-19-norandrostane-17β-ol-3-one, and was identified by its mobility on paper, sulfuric acid chromogen spectrum and reactivity with Zimmermann reagent. The other metabolite showed a slightly larger Rf value than 17α-methyl-19-norandrostane-3β, 17β-diol was easily acetylated with acetic anhydride and pyridine. This compound was identified as 17α-methy1-19-norandrostane-3α, 17β-diol from the fact that the oxidized product of this material showed identical properties with the authentic 17α-methyl-19-norandrostane-17β-ol-3-one in the above-mentioned tests.<BR>Similar experiments with 17α-ethynyl-19-nortestosterone showed the conversion of the steroid into 17α-ethynyl-19-norandrostane-17β-ol-3 one and into 17α-ethynyl-19-norandrostane-3α, 17β-diol.<BR>Incubations of these steroids with rat kidndey homogenate showed similar conversion but apparently in a smaller extent than with liver homogenate, and no additional metabolites were obtained.<BR>None of these metabolites showed progestational activity in intrauterine Clauberg assay.<BR>From these data, it was suggested that 17α-methyl-19-nortestosterone and 17α-ethynyl-19-nortestosterone were first reduced in their 4-5 double bond to form 5α-3-ketone and were further reduced in their 3-ketone to form 3-hydroxysteroids. These metabolic fates of drugs were similar to that of testosterone since this compound was reported to be reduced its 4-5 double bond first and then reduced its 3-ketone. Similar conversion has been reported with 19-nortestosterone and 17α-methyl-testosterone.<BR>Androgenic activities of these progestins might be, to some extent, related to their metabolites since the 5a-metabolites of these steroids were known as androgenic substance. But no conclusion could be drawn, from the metabolic fate, on the inefficacy of these drugs applied in utero.
- 日本内分泌学会の論文