INCREASED UDP-GLUCURONOSYLTRANSFERASE ACTIVITY AND DECREASED PROSTATE-SPECIFIC ANTIGEN PRODUCTION BY BIOCHANIN-A IN PROSTATE-CANCER CELLS

Our laboratory has characterized androgen metabolism in an androgen-re sponsive prostate cancer cell line (LNCaP) and showed that these cells accumulated intracellular testosterone primarily as glucuronidated me tabolites. Using a cell-free assay with testosterone as substrate, we showed that LNCaP had UDP-glucuronosyltransferase (UDPGT) activity. Be cause dietary factors, such as flavonoids in soy products, may reduce the risk for hormone-dependent cancers, we studied the effects of flav onoids on testosterone-UDPGT activity. LNCaP cells were exposed to sel ected flavonoids for up to 6 days. The increase in UDPGT-specific acti vity was linear over this period, Of the compounds tested, biochanin A was the most potent, with increased activity at concentration range 0 .5-50 mu M. Activities were linear for time and protein and were unaff ected by flavonoids added directly to the assay. Kinetics studies show ed no change in K-m for testosterone in the face of these large increa ses in specific activity. Cellular metabolism of testosterone reflecte d the increase in enzyme activity, Intact cells treated with biochanin A produced testosterone-glucuronide from testosterone at twice the ra te of controls. The steroid form of the UDPGT transcript was expressed in LNCaP cells and was enhanced in biochanin A-treated LNCaP cells. A dditionally, biochanin A markedly decreased prostate specific antigen (PSA) level against the effect of testosterone on PSA production, Bioc hanin A significantly decreased the testosterone-stimulated release of PSA, presumably because biochanin A increased UDPGT and increased the intracellular glucuronidation of testosterone, These studies suggest that the modulation of hormone metabolism by dietary factors may be im portant in the prevention and treatment of prostate cancer.