Androgens (testosterone and its metabolites) play a large role in the normal growth and function of the prostate. However, changes in androgen metabolism or responsiveness to androgens have been implicated in the formation of benign prostatic hypertrophy and prostate cancer. The causes of these changes are not well understood. Studies were undertaken to determine what, if any, differences in androgen metabolism occur between androgen dependent and androgen independent prostate cancer cells. In whole 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 have UDP-glucuronyl 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-glucuronyl transferase activity. Genistein and biochanin A were especially active, with the latter increasing the activity by 6 to 7-fold. In studies using Michaelis-Menten kinetics, we found the activity in stimulated cells had affinity for testosterone identical to activity from unstimulated cells. Therefore, induction of enzyme synthesis was likely. We are characterizing the induction of UDP-glucuronyl transferase in these cells at the RNA and protein levels.
