TY - JOUR T1 - EVALUATION OF 5-HYDROXYTRYPTOPHOL AND OTHER ENDOGENOUS SEROTONIN (5-HYDROXYTRYPTAMINE) ANALOGS AS SUBSTRATES FOR UDP-GLUCURONOSYLTRANSFERASE 1A6 JF - Drug Metabolism and Disposition JO - Drug Metab Dispos SP - 862 LP - 869 DO - 10.1124/dmd.32.8.862 VL - 32 IS - 8 AU - Soundararajan Krishnaswamy AU - Qin Hao AU - Lisa L. von Moltke AU - David J. Greenblatt AU - Michael H. Court Y1 - 2004/08/01 UR - http://dmd.aspetjournals.org/content/32/8/862.abstract N2 - Serotonin is a specific in vitro substrate for human UDP-glucuronosyltransferase (UGT) 1A6. In this study, the contribution of UGT1A6 to the glucuronidation of endogenous structural analogs of serotonin, including 5-hydroxytryptophol, N-acetylserotonin, and 6-hydroxymelatonin, was evaluated using available recombinant human UGT isoforms, human liver microsomes, and liver microsomes from animals that do not express functional UGT1A6 (Gunn rats and cats). Only UGT1A6 and UGT1A9 were found to glucuronidate 5-hydroxytryptophol at a concentration of 2 mM, although the glucuronidation rate with UGT1A6 was over 10 times that of UGT1A9. Km values for human liver microsomes (156, 141, and 134 μM) were most similar to that of expressed UGT1A6 (135 μM) but vastly different from that of UGT1A9 (3674 μM). 5-Hydroxytryptophol glucuronidation by human liver microsomes (n = 54) correlated well with serotonin glucuronidation (Rs = 0.83) and UGT1A6 protein content (Rs = 0.85). 5-Hydroxytryptophol also competitively inhibited serotonin glucuronidation by human liver microsomes (Ki = 291 μM) and UGT1A6 (Ki = 200 μM). N-acetylserotonin was glucuronidated most extensively by UGT1A6, although UGT1A9 and UGT1A10 showed moderate catalysis. 6-Hydroxymelatonin was glucuronidated largely by UGT1A9 and UGT1A10 but not at all by UGT1A6. Gunn rat liver glucuronidation rates for serotonin, 5-hydroxytryptophol, N-acetylserotonin, and 6-hydroxymelatonin were 11, 5, 32, and 3%, respectively, of that of normal rat liver. Cat liver microsomes did not glucuronidate serotonin, whereas relatively low activities were observed for the other indole substrates. In conclusion, these results indicate that human UGT1A6 plays a predominant role in the glucuronidation of 5-hydroxytryptophol and N-acetylserotonin, whereas 6-hydroxymelatonin is not a substrate for this enzyme. The American Society for Pharmacology and Experimental Therapeutics ER -