The focus on the metabolism of androgenic steroid hormones in the prostate has led to the use of agents which block the conversion of testosterone to dihydrotesterone as a chemopreventive approach. Another area of androgen metabolism identified as pathophysiologically important in the prostate is that of conjugation with glucuronides. Studies were undertaken to define glucuronidation mechanisms in androgen independent and androgen dependent prostate cancer cells. An important objective is to identify dietary agents which can regulate the conjugation of androgens in prostate cancer cells, to understand the mechanism for this regulation and to show either chemopreventive or chemotherapeutic effects due to these dietary agents. In cultured cell studies, we showed that added testosterone is primarily glucuronidated. Prostate cancer cells which are active in metabolizing testosterone to testosterone glucuronide were shown by assays with cell- free extracts to exhibit UDP-glucuronosyl transferase activity. This enzyme has been considered primarily to be hepatic and has not been emphasized in the prostate. Therefore the enzyme may be an important determinant of androgen responsiveness in the prostate, and its regulation by dietary compounds or nutrients was of interest. We found that certain flavonoids are active in increasing UDP- glucuronosyl transferase activity. Genistein and biochanin A were especially active with the latter increasing the activity by 6 to 7-fold. Michaelis-Menten kinetics showed unchanged affinities for substrate testosterone and suggested that the increased Vmax was due to induction of enzyme synthesis. We performed studies at the level of mRNA expression. Preliminary studies suggest that specific isoforms of UDP-GT are regulated differentially in prostate cancer cells. We are emphasizing the molecular mechanisms by which this differential regulation occurs in the prostate.
