An area of androgen metabolism identified as pathophysiologically important in the prostate is that of conjugation with glucuronides. Studies were undertaken to define glucuronidation mechanisms and to identify dietary agents which can regulate these mechanisms. We previously showed that added testosterone is primarily glucuronidated in LNCaP cells; the conversion of testosterone to testosterone glucuronide by UDP-glucuronosyl transferase (UDP-GT) was shown in cell-free extracts. This enzyme may be an important determinant of prostatic responsiveness to androgens. Thus, its regulation by dietary factors and other effectors was of interest. 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 by 6 to 7-fold. Michaelis-Menten kinetics showed unchanged affinity for testosterone. Therefore, induction of enzyme synthesis was likely. We also found that biochanin A suppressed secretion of prostate specific antigen (PSA), an androgen-responsive marker of prostatic function. Preliminary studies suggest that biochanin A decreased PSA levels by increasing the inactivation of testosterone. Thus, the activation of glucuronidation can yield functional alterations in androgen responsiveness. We also performed studies monitoring the expression of mRNA for specific isoforms of UDP-GT. Preliminary studies suggest that specific isoforms are regulated differentially. The molecular mechanisms by which this differential regulation occurs is being emphasized. In other studies, epidermal growth factor (EGF), and tumor growth factor (TGF-alpha) down-regulated UDP-GT acivity whereas the affinity for testosterone weas 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 in response to growth factors are being studied.
