Abstract 268: Regulation of the UDP-glucuronosyltransferases (UGTs) by UV exposure in human melanocytes

Abstract

Abstract The UDP-glucuronosyltransferase (UGT) family of enzymes catalyzes the glucuronidation of a variety of endogenous compounds such as bilirubin and steroid hormones, as well as xenobiotics including chemotherapeutic agents and environmental carcinogens. Glucuronidation of these substrates inactivates them by making them more hydrophilic and easily excreted. UGTs are expressed primarily in the liver, but are also expressed in several extra-hepatic tissues including prostate, breast, colon, lung, brain, kidney, bladder and ovary. We have demonstrated that three UGT family members (UGT2B7, UGT2B10 and UGT2B15) are normally expressed in human melanocytes isolated form neonatal foreskin. Further, we screened several primary and metastatic melanoma cells lines for UGT expression. Interestingly, of all the melanoma cell lines screened only WM115, a primary melanoma, had UGT expression. Again, only UGT2B7, UGT2B10 and UGT2B15 were detected. UGT expression was not detected in another primary melanoma cell line, WM3211, or in any of the four metastatic melanoma cell line assayed suggesting that loss of UGT expression occurs during melanoma progression. To elucidate if ultraviolet (UV) light could be the underlying cause to the disappearance of UGTs in melanoma progression, human melanocytes were subjected to UV-B radiation at low and high (sunburn) doses. Melanocytes were collected at 1, 5 and 24 Hrs post UV-B treatment and UGT expression was analyzed by quantitative real-time PCR. Expression of UGT2B7, UGT2B10 and UGT2B15 all was significantly reduced in response to both low and high dose UV-B. In general, loss of UGT expression was observed even at 1 hour after exposure, reached maximal low levels at 5 hours and started to return to normal levels at 24 hours post exposure. We hypothesize that reduction of UGT expression in melanocytes following a sunburn would increase an individuals risk for melanoma since the UGTs detoxify environmental carcinogens. This hypothesis is consistent with a causative role for UV in melanoma in which ‘classical’ UV-induced DNA damage is not observed; a problem that has long puzzled investigators. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 268. doi:1538-7445.AM2012-268