The conjugation of androgens in the prostate may be important for regulating hormonal response. Studies were undertaken to define glucuronidation mechanisms in prostate cancer cells and to identify dietary agents which can regulate these mechanisms. We previously showed that LNCaP cells glucuronidate testosterone; the conversion of testosterone to testosterone glucuronide by UDP-glucuronosyl transferase (UDP-GT) was shown in cell-free extracts. We found that certain flavonoids were active in increasing UDP-GT activity. Genistein and biochanin A were especially active with the latter increasing the activity 6 to 7-fold. The induction of the steroid isoform of UDP-GT was documented at the mRNA level. We also found that biochanin A suppressed secretion of prostate specific antigen (PSA) by increasing the inactivation of testosterone. A decrease in androgen response at the level of the androgen receptor (AR) was ruled out since the capacity of AR to bind androgen was, in fact, slightly increased. 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. In other studies, epidermal growth factor (EGF), and tumor growth factor (TGF- a) down-regulated UDP-GT activity whereas the affinity for testosterone was not affected. These studies suggest that testosterone: UDP-GT is regulated reciprocally with growth and the degradation of testosterone is decreased when cells are stimulated by EGF. The differential expression of specific isozymes of UDP-GT in response to growth factors are being studied. Finally, we examined the biochanin A modulation of pro-oxidant/ antioxidant shift because androgens can induce oxidative stress in LNCaP cells. We found that levels of oxidative stress could be decreased with biochanin A treatment. We are investigating the possibility that this reduction of oxidative stress is due to the inactivation of testosterone.
