The animals were allowed to adjust to their new environment for at least 3 days before the testing

alyzes the glucuronidation of a wide range of xenobiotic and endogenous compounds. UGTs conjugate a glucuronic acid moiety to their substrates, altering the biological properties of the substrate and enhancing its excretion in urine or bile. In general, glucuronidation converts substrates into less bioactive, more water soluble products facilitating their removal from the body. In this manner, the UGTs are integrally involved in the detoxification of many carcinogens, the clearance of drugs and the metabolism of a variety of endogenous substrates such as bilirubin, steroid hormones and bioactive lipids. There are 19 functional human UGTs classified into three subfamilies based upon structural and amino acid sequence homology, UGT1A, UGT2A and UGT2B. The UGTs are membrane bound enzymes largely localized to the endoplasmic reticulum. Substrate specificity varies greatly between family members, with broad overlap, and their substrate specificity can be altered by posttranslational modifications such as phosphorylation. Although UGTs are primarily expressed in liver, they also play vital roles in other tissues in the body. For example, UGT2B15 and UGT2B17 are expressed in the prostate where they regulate local androgen levels through glucuronidation and UGT1A10 and UGT2B7 are expressed in the breast where they regulate estrogens. There is also ample evidence that the UGTs play important roles in the aerodigestive tract, gastrointestinal tract, lung, colon, bladder, kidneys and brain. However, the role of the UGTs in skin, the largest organ in the body, has yet to be investigated. Melanoma is one of the fastest growing tumor types in the United States and the number of cases worldwide has doubled in the past 30 years. Melanoma, which arises from melanocytes, is an extremely aggressive tumor that invades the vascular and lymphatic systems to form tumors elsewhere in the body. Melanoma is a particularly resilient cancer, accounting for only 4% of all skin cancers but responsible for 80% of skin cancer deaths. Further, only 14% of patients with metastatic melanoma survive for 5 years. Systemic therapy approaches have achieved minimal success against metastatic melanoma resulting in only a few FDAapproved treatments. Interferon-a2b, interleukin-2 and temozolomide have all demonstrated limited efficacy with response rates generally under 15% in the short term with no Re-Expression of UGTs in Melanoma clear effect on melanoma-related mortality. However, the recent success of the specific BRAF mutant inhibitor vemurafenib in a Phase 1 clinical trail is very promising. An estimated progression free survival of 7 months was reported among all patients harboring the BRAF V600E mutation, which is present in approximately 50% of all melanomas. However, the excitement for vemurafenib as a single agent has been tempered somewhat since acquired CJ-023423 web resistance is already being observed. Thus, understanding the mechanism of resistance to chemotherapy that melanoma cells employ is paramount to combating this deadly disease. The goal of the present study was to characterize the expression and function of UGTs in melanocytes and melanoma and to examine the potential role of UGTs in drug resistance. Evidence presented here reveals three UGT family members, UGT2B7, UGT2B10 and UGT2B15, as being normally expressed in human melanocytes isolated from neonatal foreskins. The same three UGTs were found to be expressed in the primary melanoma cell line WM115. Interestingly