The (+)- and (-)-gossypols potently inhibit both 3beta-hydroxysteroid dehydrogenase and 17beta-hydroxysteroid dehydrogenase 3 in human and rat testes.

Abstract

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.

• Authors: Guo-Xin Hu, Hong-Yu Zhou, Xing-Wang Li, Bing-Bing Chen, Ye-Chen Xiao, Qing-Quan Lian, Guang Liang, Howard H Kim, Zhi-Qiang Zheng, Dianne O Hardy, Ren-Shan Ge
• Journal: The Journal of steroid biochemistry and molecular biology (J Steroid Biochem Mol Biol) Vol. 115 Issue 1-2 Pg. 14-9 (May 2009) ISSN: 1879-1220 [Electronic] England
• PMID: 19429456 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Antineoplastic Agents
• 17-Hydroxysteroid Dehydrogenases
• 17beta-hydroxysteroid dehydrogenase type 3
• 3 (or 17)-beta-hydroxysteroid dehydrogenase
• Gossypol

Topics

• 17-Hydroxysteroid Dehydrogenases (antagonists & inhibitors)
• Animals
• Antineoplastic Agents (pharmacology)
• Binding, Competitive
• Gossypol (pharmacology)
• Humans
• Inhibitory Concentration 50
• Male
• Rats
• Species Specificity
• Testis (enzymology, metabolism)