Cyproterone acetateの培養外陰部皮膚線維芽細胞aromatase活性に及ぼす影響に関する研究:(主として細胞内aromatase活性の調節機序について)
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Cyproterone acetate (CA), a well-known competitive antiandrogen, has been used for the treatment of precocious puberty, prostatic adenocarcinoma, hirsutism and hypersexuality. However, there have been some reports of troublesome gynecomastia developing during the use of this drug. It was, therefore, of interest to investigate the effect of CA on peripheral aromatization, since it is the major source of circulating estrogens in men. Our recent studies of aromatase activity in human skin fibroblasts demonstrated that the skin is an important site of extraglandular aromatase activity in men and suggested that these cells might provide a valuable new system in which to study the enzyme. Estrogen formation was assayed by the [<SUP>3</SUP>H] H<SUB>2</SUB> O technique, after 3h incubation of the cells with androste-nedione. The initial experiment was designed to test the effect of CA (10<SUP>-8</SUP> to 10<SUP>-5</SUP>M) on baseline aromatase activity during a 12h preincubation in the presence of fetal bovine serum (FBS). Baseline aromatase activity was not affected by the presence of CA, whereas medroxyprogesterone acetate, a similar synthetic progestogen, induced a 2-fold stimulation of aromatase activity at a concentration of 10<SUP>-5</SUP>M. In cells preincubated with dexamethasone (DEX) in the presence of FBS, aromatase activity was stimulated markedly. When the cells were preincubated in the medium containing FBS with DEX (2.5×10<SUP>-7</SUP>M) in the presence of CA (10<SUP>-7</SUP>to 10<SUP>-4</SUP>M), DEX-stimulated levels of aromatase activity were inhibited by CA in a dose-dependent fashion. A competitive binding assay using [<SUP>3</SUP>H] DEX, showed that CA was able to compete with DEX for glucocorticoid receptor and the relative binding affinity of CA was approximately 50 times less than DEX. This suggested that the inhibitory effect of CA was due to competition with DEX for receptor binding. Aromatase activity was also stimulated by (Bu) <SUB>2</SUB> cAMP (1mM) in the absence of FBS. The stimulatory effect of (Bu) <SUB>2</SUB> cAMP was maximal after 12-24h of preincubation, and this level was maintained for 60h. Similar to the DEX stimulation, stimulation of aromatase activity by (Bu) <SUB>2</SUB> cAMP required both RNA and protein synthesis, since the stimulatory effect of (Bu) <SUB>2</SUB> cAMP was abolished by co-preincubation with cycloheximide or actinomycin D. When CA was present during either the 12h preincubation or assay incubation, no difference was found in the (Bu) <SUB>2</SUB> cAMP-stimulated levels of aromatase activity. On the other hand, the nonaromatizable androgen dihydrotestosterone (DHT) (10<SUP>-8</SUP> to 10<SUP>-6</SUP>M) inhibited the stimulation of aromatase activity by (Bu) <SUB>2</SUB> cAMP in a dose-dependent fashion. The inhibitory effect of DHT on (Bu) <SUB>2</SUB> cAMP stimulation of aromatase activity was prevented by co-preincubation with CA (10<SUP>-5</SUP>M). These findings suggest that CA acts to increase aromatase activity in skin fibroblasts by preventing the inhibitory effect of androgen as antiandrogen under physiologic conditions, although CA inhibits the glucocorticoid stimulation of aromatase activity.
- 一般社団法人 日本内分泌学会の論文
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