DIFFERENTIAL REGULATION OF 2 URIDINE DIPHOSPHO-GLUCURONOSYLTRANSFERASES, UGT2B15 AND UGT2B17, IN HUMAN PROSTATE LNCAP CELLS

Although androgens are important regulators in the prostate, other eff ecters such as growth factors may also act to maintain normal function of the gland. Human prostate and human prostate cancer LNCaP cells ex press steroid conjugating uridine diphospho-glucuronosyltransferase (U GT) enzymes, and it was shown that the level of UGT activities and tra nscripts is down-regulated by androgens, especially dihydrotestosteron e (DHT). In the present study, we examined the interaction between and rogen, epidermal growth factor (EGF), and steroid UGT enzymes. The for mation of DHT glucuronide (DHT-G) was inhibited by 47% when LNCaP cell s were treated for 6 days with 10 ng/ml of EGF. Northern blot analysis also demonstrated a decrease in the steady-state level of UGT2B trans cripts. Treatment with both DHT (0.5 nM) and EGF (10 ng/ml) caused a g reater decrease of DHT glucuronidation and UGT2B messenger RNA levels than when the cells were treated with either compound alone. RNase pro tection assays showed that treatment with DHT and EGF caused a specifi c decrease of UGT2B17 transcript in LNCaP cells treated, however, the level of UGT2B15 messenger RNA was not affected. As well, Western blot analysis demonstrated a diminution of UGT2B17 protein level in respon se to DHT and EGF. Thew results demonstrate a differential regulation of different isoforms of steroid conjugating UGTs present in human pro state LNCaP cells. UGT2B17 was shown to be more labile than UGT2B15, i ndicating that regulation of UGT2B17 expression would lead to a more r apid change in the level of glucuronidated steroids.