期刊
JOURNAL OF STEROID BIOCHEMISTRY AND MOLECULAR BIOLOGY
卷 115, 期 1-2, 页码 14-19出版社
PERGAMON-ELSEVIER SCIENCE LTD
DOI: 10.1016/j.jsbmb.2009.02.004
关键词
Steroids; Testosterone; Competitive inhibition; Hydroxysteroid dehydrogenase
资金
- EUNICE KENNEDY SHRIVER NATIONAL INSTITUTE OF CHILD HEALTH &HUMAN DEVELOPMENT [R01HD050570] Funding Source: NIH RePORTER
- NICHD NIH HHS [HD050570] Funding Source: Medline
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 3 beta-hydroxysteroid dehydrogenase (3 beta-HSD)and 17 beta-HSD isoform 3 (17 beta-HSD3) in human and rat testes. Gossypol enantiomers were more potent inhibitors of rat 3 beta-HSD with IC(50)s of similar to 0.2 mu M compared to 3-5 mu M in human testes. However, human 17 beta-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. were species- and enantiomer-specific differences in the sensitivity of the inhibition of 17 beta-HSD3. Gossypol enantiomers competitively inhibited both 3 beta-HSD and 17 beta-HSD3 by competing for the cofactor binding sites of these enzymes. Gossypol enantiomers, fed orally to rats (20 mg/kg), inhibited 3 beta-HSD but not 17 beta-HSD3. This finding was consistent with the in vitro data, in which rat 30-HSD was more sensitive to gossypol inhibition than rat 17 beta-HSD3. As the reverse was true for the human enzymes, gossypol might be useful for treating metastatic prostate cancer. (c) 2009 Elsevier Ltd. All rights reserved.
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