QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

This Article Full Text Full Text (PDF) Submit a response Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Krishnaswamy, S. Articles by Court, M. H. Search for Related Content PubMed PubMed Citation Articles by Krishnaswamy, S. Articles by Court, M. H.

EVALUATION OF 5-HYDROXYTRYPTOPHOL AND OTHER ENDOGENOUS SEROTONIN (5-HYDROXYTRYPTAMINE) ANALOGS AS SUBSTRATES FOR UDP-GLUCURONOSYLTRANSFERASE 1A6

Comparative and Molecular Pharmacogenetics Laboratory (S.K., Q.H., M.H.C.) and Clinical Pharmacology Laboratory (L.L.v.M., D.J.G.), Department of Pharmacology and Experimental Therapeutics, Tufts University School of Medicine, Boston, Massachusetts

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. K_m 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 (R_s = 0.83) and UGT1A6 protein content (R_s = 0.85). 5-Hydroxytryptophol also competitively inhibited serotonin glucuronidation by human liver microsomes (K_i = 291 µM) and UGT1A6 (K_i = 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.

This article has been cited by other articles:

				J. Tojcic, M.-O. Benoit-Biancamano, M. H. Court, R. J. Straka, P. Caron, and C. Guillemette In Vitro Glucuronidation of Fenofibric Acid by Human UDP-Glucuronosyltransferases and Liver Microsomes Drug Metab. Dispos., November 1, 2009; 37(11): 2236 - 2243. [Abstract] [Full Text] [PDF]

				H.-X. Liu, Y. Liu, J.-W. Zhang, W. Li, H.-T. Liu, and L. Yang UDP-Glucuronosyltransferase 1A6 Is the Major Isozyme Responsible for Protocatechuic Aldehyde Glucuronidation in Human Liver Microsomes Drug Metab. Dispos., August 1, 2008; 36(8): 1562 - 1569. [Abstract] [Full Text] [PDF]

				D. Li, S. Fournel-Gigleux, L. Barre, G. Mulliert, P. Netter, J. Magdalou, and M. Ouzzine Identification of Aspartic Acid and Histidine Residues Mediating the Reaction Mechanism and the Substrate Specificity of the Human UDP-glucuronosyltransferases 1A J. Biol. Chem., December 14, 2007; 282(50): 36514 - 36524. [Abstract] [Full Text] [PDF]

				S. Krishnaswamy, Q. Hao, A. Al-Rohaimi, L. M. Hesse, L. L. von Moltke, D. J. Greenblatt, and M. H. Court UDP Glucuronosyltransferase (UGT) 1A6 Pharmacogenetics: II. Functional Impact of the Three Most Common Nonsynonymous UGT1A6 Polymorphisms (S7A, T181A, and R184S) J. Pharmacol. Exp. Ther., June 1, 2005; 313(3): 1340 - 1346. [Abstract] [Full Text] [PDF]

				S. Krishnaswamy, Q. Hao, A. Al-Rohaimi, L. M. Hesse, L. L. von Moltke, D. J. Greenblatt, and M. H. Court UDP Glucuronosyltransferase (UGT) 1A6 Pharmacogenetics: I. Identification of Polymorphisms in the 5'-Regulatory and Exon 1 Regions, and Association with Human Liver UGT1A6 Gene Expression and Glucuronidation J. Pharmacol. Exp. Ther., June 1, 2005; 313(3): 1331 - 1339. [Abstract] [Full Text] [PDF]