标题：Gossypol inhibits 5 alpha-reductase 1 and 3 alpha-hydroxysteroid dehydrogenase: Its possible use for the treatment of prostate cancer
作者：Cao, Shuyan; Wang, Guimin; Ge, Fei; Li, Xiaoheng; Zhu, Qiqi; Ge, Ren-Shan; Wang, Yunshan
作者机构：[Cao, Shuyan; Wang, Yunshan] Shandong Univ, Jinan Cent Hosp, Cent Lab, 105 Jiefang Rd, Jinan 250013, Shandong, Peoples R China.; [Cao, Shuyan; Li, X 更多
通讯作者：Wang, YS;Ge, RS;Ge, RS
通讯作者地址：[Wang, YS]Shandong Univ, Jinan Cent Hosp, Cent Lab, 105 Jiefang Rd, Jinan 250013, Shandong, Peoples R China;[Ge, RS]Wenzhou Med Univ, Yuying Childrens 更多
关键词：Gossypol; 5 alpha-reductase 1; 3 alpha-hydroxysteroid dehydrogenase;; Retinol dehydrogenase 2; Mode of action
摘要：Gossypol is a yellow polyphenol isolated from cotton seeds. It has the antitumor activity and it is being tested to treat prostate cancer. However, its underlying mechanisms are still not well understood. The present study investigated the inhibitory effects of gossypol acetate on rat 5 alpha-reductase 1, 3 alpha-hydroxysteroid dehydrogenase, and retinol dehydrogenase 2 for androgen metabolism. Rat 5 alpha-reductase 1, 3 alpha-hydroxysteroid dehydrogenase, and retinol dehydrogenase 2 were expressed in COS-1 cells. Immature Leydig cells that contain these enzymes were isolated from 35-day-old male Sprague Dawley rats. The potency and mode of action of gossypol acetate to inhibit these enzymes in both enzyme-expressed preparations and immature Leydig cells were examined. Molecular docking study of gossypol on the crystal structure of 3 alpha-hydroxysteroid dehydrogenase was performed. Gossypol acetate inhibited 5 alpha-reductase 1 and 3 alpha-hydroxysteroid dehydrogenase with IC50 values of 3.33 +/- 0.07 and 0.52 +/- 0.06 x 10(-6) M in the expressed enzymes as well as 8.512 +/- 0.079 and 1.032 +/- 0.068 x 10(-6) M in intact rat immature Leydig cells, respectively. Gossypol acetate inhibited rat 5 alpha-reductase 1 in a noncompetitive mode and 3 alpha-hydroxysteroid dehydrogenase in a mixed mode when steroid substrates were supplied. Gossypol acetate weakly inhibited retinol dehydrogenase 2 with IC50 value over 1 x 10(-4 )M. Molecular docking analysis showed that gossypol partially bound to the steroid-binding site of the crystal structure of rat 3 alpha-hydroxysteroid dehydrogenase. Gossypol acetate is a potent inhibitor of rat 5 alpha-reductase 1 and 3 alpha-hydroxysteroid dehydrogenase, possibly inhibiting the formation of androgen in the prostate cancer cells.