Increased UDP-glucuronosyltransferase activity and decreased prostate specific antigen production by biochanin A in prostate cancer cells

Abstract

Our laboratory has characterized androgen metabolism in an androgen-responsive prostate cancer cell line (LNCaP) and showed that these cells accumulated intracellular testosterone primarily as glucuronidated metabolites. Using a cell-free assay with testosterone as substrate, we showed that LNCaP had UDP-glucuronosyltransferase (UDPGT) activity. Because dietary factors, such as flavonoids in soy products, may reduce the risk for hormone-dependent cancers, we studied the effects of flavonoids on testosterone-UDPGT activity. LNCaP cells were exposed to selected flavonoids for up to 6 days. The increase in UDPGT-specific activity was linear over this period. Of the compounds tested, biochanin A was the most potent, with increased activity at concentration range 0.5-50 microM. Activities were linear for time and protein and were unaffected by flavonoids added directly to the assay. Kinetics studies showed no change in Km for testosterone in the face of these large increases in specific activity. Cellular metabolism of testosterone reflected the increase in enzyme activity. Intact cells treated with biochanin A produced testosterone-glucuronide from testosterone at twice the rate of controls. The steroid form of the UDPGT transcript was expressed in LNCaP cells and was enhanced in biochanin A-treated LNCaP cells. Additionally, biochanin A markedly decreased prostate specific antigen (PSA) level against the effect of testosterone on PSA production. Biochanin 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 important in the prevention and treatment of prostate cancer.