The (+)- and (-)-gossypols potently inhibit both 3beta-hydroxysteroid dehydrogenase and 17beta-hydroxysteroid dehydrogenase 3 in human and rat testes.
Androgen deprivation is commonly used in the treatment of metastatic prostate cancer. The (-)-gossypol enantiomer has been demonstrated as an effective inhibitor of Bcl-2 in the treatment of prostate cancer. However, the mechanism of gossypol as an inhibitor of androgen biosynthesis is not clear. The present study compared (+)- and (-)-gossypols in the inhibition of 3beta-hydroxysteroid dehydrogenase (3beta-HSD) and 17beta-HSD isoform 3 (17beta-HSD3) in human and rat testes. Gossypol enantiomers were more potent inhibitors of rat 3beta-HSD with IC(50)s of approximately 0.2microM compared to 3-5microM in human testes. However, human 17beta-HSD3 was more sensitive to inhibition by gossypol enantiomers, with IC(50)s of 0.36+/-0.09 and 1.13+/-0.12 for (-)- and (+)-gossypols, respectively, compared to 3.43+/-0.46 and 10.93+/-2.27 in rat testes. There were species- and enantiomer-specific differences in the sensitivity of the inhibition of 17beta-HSD3. Gossypol enantiomers competitively inhibited both 3beta-HSD and 17beta-HSD3 by competing for the cofactor binding sites of these enzymes. Gossypol enantiomers, fed orally to rats (20mg/kg), inhibited 3beta-HSD but not 17beta-HSD3. This finding was consistent with the in vitro data, in which rat 3beta-HSD was more sensitive to gossypol inhibition than rat 17beta-HSD3. As the reverse was true for the human enzymes, gossypol might be useful for treating metastatic prostate cancer.
Institute of Molecular Toxicology & Pharmacology, Wenzhou Medical College, Zhejiang, PR China.
Guo-Xin
GX
Hu
Hong-Yu
HY
Zhou
Xing-Wang
XW
Li
Bing-Bing
BB
Chen
Ye-Chen
YC
Xiao
Qing-Quan
QQ
Lian
Guang
G
Liang
Howard H
HH
Kim
Zhi-Qiang
ZQ
Zheng
Dianne O
DO
Hardy
Ren-Shan
RS
Ge
D015067:17-Hydroxysteroid Dehydrogenases / Q000037:antagonists & inhibitors*; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D001667:Binding, Competitive; D006072:Gossypol / Q000494:pharmacology*; D006801:Humans; D020128:Inhibitory Concentration 50; D008297:Male; D051381:Rats; D013045:Species Specificity; D013737:Testis / Q000201:enzymology* / Q000378:metabolism
D000970:Antineoplastic Agents; D015067:17-Hydroxysteroid Dehydrogenases; C476565:17beta-hydroxysteroid dehydrogenase type 3; C044256:3 (or 17)-beta-hydroxysteroid dehydrogenase; D006072:Gossypol