The (+)- and (−)-gossypols potently inhibit both 3β-hydroxysteroid dehydrogenase and 17β-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 3β-hydroxysteroid dehydrogenase (3β-HSD) and 17β-HSD isoform 3 (17β-HSD3) in human and rat testes. Gossypol enantiomers were more potent inhibitors of rat 3β-HSD with IC50s of ∼0.2 μM compared to 3-5 μM in human testes. However, human 17β-HSD3 was more sensitive to inhibition by gossypol enantiomers, with IC50s 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 17β-HSD3. Gossypol enantiomers competitively inhibited both 3β-HSD and 17β-HSD3 by competing for the cofactor binding sites of these enzymes. Gossypol enantiomers, fed orally to rats (20 mg/kg), inhibited 3β-HSD but not 17β-HSD3. This finding was consistent with the in vitro data, in which rat 3β-HSD was more sensitive to gossypol inhibition than rat 17β-HSD3. As the reverse was true for the human enzymes, gossypol might be useful for treating metastatic prostate cancer.