Androgen inactivation by conjugation mechanisms may be important for regulating the hormonal response. Studies were undertaken to define glucuronidation in prostate cancer cells and to identify regulatory mechanisms. We previously showed that LNCaP cells conjugate testosterone by glucuronidation; activity of UDP-glucuronosyl transferase (UDPGT) was characterized in cell-free extracts. We found that LNCaP cells treated with certain flavonoids and isoflavones showed increased UDPGT activity for testosterone. Genistein and biochanin A were especially active with the latter increasing the activity 6 to 7- fold. The biochanin A induction of UDPGT was documented by the monitoring of mRNA for a specific steroid-glucuronidating isoform of UDPGT (UGT2B15) was documented at the mRNA level. By contrast, mRNA expression of a phenolic form of UDPGT, UGT1F, was not detectible in LNCaP cells with or without treatment by biochanin A. Relevant to prostate physiology, treatment with biochanin A suppressed secretion of prostate specific antigen (PSA) in LNCaP cells by increasing the inactivation of testosterone. A possible decrease in androgen receptor (AR) was directly ruled out. To our knowledge, this is the first demonstration that dietary factors can alter the androgen response pathway in a target tissue by altering its metabolism of androgens.The generation of reactive oxygen species (ROS) has been associated in either mitogenic activation or, on the other hand, oxidative damage and apoptosis. We found that LNCaP cells exposed to testosterone generated ROS in a concentration- dependent fashion. Interestingly, treatment with biochanin A markedly decreased the testosterone effect. Since mitogenic growth factors may augment ROS generation, we tested EGF, IGF-I and IGF-II on ROS generation in LNCaP cells, all of which were without effect. PC-3 and DU-145 cells are prostate cancer cells without androgen receptors and testosterone had no effect on ROS generation in these cells. Therefore, we considered that PSA production, an androgen receptor-dependent effect of testosterone, might be involved in the ROS generation. Importantly, PSA increased ROS generation not only in LNCaP cells but also in PC-3 and DU-145 cells. We conclude that the increase in ROS in response to testosterone may be related to the secretion of PSA. Just how PSA increases ROS formation in prostate cancer cells is currently being studied. - Androgens, Detoxifiation, dietary factors, Growth factors, Phytochemicals, Prostate cancer,
