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

This Article Full Text Full Text (PDF) All Versions of this Article: jpet.105.091900v1 315/3/1143    most recent Submit a response Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Citation Map 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 Finel, M. Articles by Radominska-Pandya, A. Search for Related Content PubMed PubMed Citation Articles by Finel, M. Articles by Radominska-Pandya, A.

CELLULAR AND MOLECULAR

Human UDP-Glucuronosyltransferase 1A5: Identification, Expression, and Activity

Viikki Drug Discovery and Development Technologies Center, Faculty of Pharmacy, University of Helsinki, Helsinki, Finland (M.F.); Department of Biochemistry and Molecular Biology, University of Arkansas for Medical Sciences, Little Rock, Arkansas (X.L., S.B., A.R.-P.); and Department of Clinical Pharmacology, Flinders University, Flinders Medical Centre, Bedford Park, South Australia, Australia (D.G.-S., P.I.M.)

The human UDP-glucuronosyltransferase (UGT) subfamily 1A includes nine genes. The expression of all the UGT1A isoforms, apart from UGT1A5, has been reported previously. We have now detected a low basal level of UGT1A5 expression in cultured human hepatocytes, and treatment with rifampicin or 3-methylcholanthrene increased the level of UGT1A5 mRNA. Low-level UGT1A5 expression was also found in HepG2 and Caco-2 cells as well as human liver. Furthermore, UGT1A5 expression has been detected in various segments of the intestine from human donors, revealing high interindividual variability in its level and distribution along the intestine. Full-length UGT1A5 cDNA was isolated from Caco-2 cells that had been transfected with the pregnane X receptor and treated with rifampicin. Recombinant UGT1A5, expressed in baculovirus-infected insect cells, exhibited very low rates of 4-methylumbelliferone and scopoletin glucuronidation, whereas 1-hydroxypyrene was a much better substrate for it. UGT1A5 did not glucuronidate 4-aminobiphenyl, a good substrate for the highly homologous enzymes UGT1A4 and UGT1A3. However, replacing the first 110 amino acids of UGT1A5, a region that may be involved in substrate binding, with the counterpart segment from UGT1A4 did not increase the 4-aminobiphenyl glucuronidation activity. Collectively, this work demonstrates for the first time that the human UGT1A5 is expressed in several tissues, is inducible, and is catalytically active.

Address correspondence to: Dr. Moshe Finel, Viikki DDTC, Faculty of Pharmacy, University of Helsinki, P.O. Box 56 (Viikinkaari 5E), 00014 University of Helsinki, Finland. E-mail: moshe.finel{at}helsinki.fi

This article has been cited by other articles:

				N. Hariparsad, X. Chu, J. Yabut, P. Labhart, D. P. Hartley, X. Dai, and R. Evers Identification of pregnane-X receptor target genes and coactivator and corepressor binding to promoter elements in human hepatocytes Nucleic Acids Res., March 1, 2009; 37(4): 1160 - 1173. [Abstract] [Full Text] [PDF]

				S. Ohno and S. Nakajin Determination of mRNA Expression of Human UDP-Glucuronosyltransferases and Application for Localization in Various Human Tissues by Real-Time Reverse Transcriptase-Polymerase Chain Reaction Drug Metab. Dispos., January 1, 2009; 37(1): 32 - 40. [Abstract] [Full Text] [PDF]

				H. Yamanaka, M. Nakajima, M. Katoh, and T. Yokoi Glucuronidation of Thyroxine in Human Liver, Jejunum, and Kidney Microsomes Drug Metab. Dispos., September 1, 2007; 35(9): 1642 - 1648. [Abstract] [Full Text] [PDF]

				S. Kaivosaari, P. Toivonen, L. M. Hesse, M. Koskinen, M. H. Court, and M. Finel Nicotine Glucuronidation and the Human UDP-Glucuronosyltransferase UGT2B10 Mol. Pharmacol., September 1, 2007; 72(3): 761 - 768. [Abstract] [Full Text] [PDF]

				Z. Wen, M. N. Tallman, S. Y. Ali, and P. C. Smith UDP-Glucuronosyltransferase 1A1 Is the Principal Enzyme Responsible for Etoposide Glucuronidation in Human Liver and Intestinal Microsomes: Structural Characterization of Phenolic and Alcoholic Glucuronides of Etoposide and Estimation of Enzyme Kinetics Drug Metab. Dispos., March 1, 2007; 35(3): 371 - 380. [Abstract] [Full Text] [PDF]

				D. A. Gardner-Stephen and P. I. Mackenzie Isolation of the UDP-Glucuronosyltransferase 1A3 and 1A4 Proximal Promoters and Characterization of Their Dependence on the Transcription Factor Hepatocyte Nuclear Factor 1{alpha} Drug Metab. Dispos., January 1, 2007; 35(1): 116 - 120. [Abstract] [Full Text] [PDF]

				T. Sten, S. Qvisen, P. Uutela, L. Luukkanen, R. Kostiainen, and M. Finel Prominent but Reverse Stereoselectivity in Propranolol Glucuronidation by Human UDP-Glucuronosyltransferases 1A9 and 1A10 Drug Metab. Dispos., September 1, 2006; 34(9): 1488 - 1494. [Abstract] [Full Text] [PDF]