Characterization of UDP-glucuronosyltransferases active on steroid hormones

In recent years, the enzymes which are involved in the formation of DHT in steroid target tissues have been well investigated, however, enzymes respon sible for the catabolism and elimination of steroids in these tissues, in p articular the uridine diphospho-glucuronosyltransferase (UGT) family of enz ymes, have received much less attention. We have recently demonstrated that human and monkey are unique in having high plasma levels of C19 steroid gl ucuronides. These circulating conjugates have been proposed to reflect the peripheral conversion of adrenal and gonadal C19 steroids to potent androge ns, especially DHT. In humans, the presence of steroid UGT activities is fo und in the liver and several extrahepatic tissues including the prostate, m ammary gland and ovary. In addition, UGT activities were observed in breast and prostate tumor cell lines such as MCF-7 and LNCaP, respectively. In ag reement with the presence of steroid conjugating enzymes in extrahepatic ti ssues, UGT cDNA clones, which encode steroid conjugating proteins, have bee n isolated from libraries constructed from human and monkey prostate mRNA. The presence of UGT transcripts and proteins in extrahepatic tissues in bot h species, as determined by Northern blot, ribonuclease protection, specifi c RT-PCR, in situ hybridization, Western blot and immunocytochemistry analy sis, indicate the relevance of steroid glucuronidation in tissues other tha n the liver. Knowing that both the human prostate and the human prostate ca ncer LNCaP cell line express steroid metabolizing proteins, including UGT e nzymes, regulation of UGT mRNA and protein levels, as well as promoter acti vity was studied in these cells. The results demonstrate a differential reg ulation between the two highly related isoforms UGT2B15 and UGT2B17, where only the expression of UGT2B17 was affected following treatments of LNCaP c ells with androgens, growth factors or cytokines. Steroid conjugation by UG T enzymes is potentially involved in hormone inactivation in steroid target tissues, thus modifications in UGT expression levels may influence hormona l responses. (C) 1999 Elsevier Science Ltd. All rights reserved.