HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS		QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

J. Biol. Chem., Vol. 280, Issue 45, 37547-37557, November 11, 2005

This Article Full Text Full Text (PDF) All Versions of this Article: 280/45/37547    most recent M506683200v1 Submit a Letter to Editor Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Chen, S. Articles by Tukey, R. H. Search for Related Content PubMed PubMed Citation Articles by Chen, S. Articles by Tukey, R. H. Social Bookmarking                      What's this?

Tissue-specific, Inducible, and Hormonal Control of the Human UDP-Glucuronosyltransferase-1 (UGT1) Locus^*

Shujuan Chen, Deirdre Beaton, Nghia Nguyen, Kathy Senekeo-Effenberger, Erin Brace-Sinnokrak, Upendra Argikar, Rory P. Remmel, Jocelyn Trottier¶1, Olivier Barbier¶, Joseph K. Ritter||, and Robert H. Tukey2

From the Laboratory of Environmental Toxicology, Departments of Pharmacology, Chemistry and Biochemistry, University of California, San Diego, La Jolla, California 92093-0722, the ^¶Molecular Endocrinology and Oncology Research Center, Centre Hospitalier del'Université Laval Research Center and the Faculty of Pharmacy, Laval University, Québec, Québec G1K 7P4, Canada, the Department of Medicinal Chemistry, College of Pharmacy, University of Minnesota, Minneapolis, Minnesota 55455, and the ^||Department of Pharmacology and Toxicology, Virginia Commonwealth University, Medical College of Virginia, Richmond, Virginia 23298-0613

The human UDP-glucuronosyltransferase 1 (UGT1) locus spans nearly 200 kb on chromosome 2 and encodes nine UGT1A proteins that play a prominent role in drug and xenobiotic metabolism. Transgenic UGT1 (Tg-UGT1) mice have been created, and it has been demonstrated that tissue-specific and xenobiotic receptor control of the UGT1A genes is influenced through circulating humoral factors. In Tg-UGT1 mice, the UGT1A proteins are differentially expressed in the liver and gastrointestinal tract. Gene expression profiles confirmed that all of the UGT1A genes can be targeted for regulation by the pregnane X receptor activator pregnenolone-16-carbonitrile (PCN) or the Ah receptor ligand 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD). In addition, the selective induction of glucuronidation activity toward lamotrigine, ethinyl estradiol, chenodeoxycholic acid, and lithocholic acid by either PCN or TCDD in small intestine from Tg-UGT1 mice corresponded to expression of the locus in this tissue. Induction of UGT1A1 by PCN and TCDD is believed to be highly dependent upon glucocorticoids, because submicromolar concentrations of dexamethasone actively promote PCN and TCDD induction of UGT1A1 in Tg-UGT1 primary hepatocytes. The role of hormonal control of the UGT1 locus was further verified in pregnant and nursing Tg-UGT1 mice. In maternal 14-day post-conception Tg-UGT1mice, liver UGT1A1, UGT1A4, and UGT1A6 were induced, with the levels returning to near normal by birth. However, maternal liver UGT1A4 and UGT1A6 were dramatically elevated and maintained after birth, indicating that these proteins may play a critical role in maternal metabolism during lactation. With expression of the UGT1 locus confirmed in a variety of mouse tissues, these results suggested that the Tg-UGT1 mice will be a useful model to examine the regulatory and functional properties of human glucuronidation.

Received for publication, June 20, 2005 , and in revised form, September 8, 2005.

^* This work was supported in part by United States Public Health Service Grants GM49135, and ES10337 (to R. H. T.), ES07762 (to J. K. R.), P50-NS16308 (to R. P. R.), Canadian Institutes of Health Research Grant MOP 118446, and the Fonds de la Recherche en Santé du Québec (to O. B.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ Recipient of a scholarship from the "Fond pour l'Enseignement et la Recherche" from the Faculty of Pharmacie, Laval University.

² To whom correspondence should be addressed: University of California, San Diego, Leichtag Biomedical Research Bldg., La Jolla, CA 92093-0722. Tel.: 858-822-0288; Fax: 858-822-0363, E-mail: rtukey{at}ucsd.edu.

CiteULike    Complore    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this?

This article has been cited by other articles:

				D. B. Buckley and C. D. Klaassen Induction of Mouse UDP-Glucuronosyltransferase mRNA Expression in Liver and Intestine by Activators of Aryl-Hydrocarbon Receptor, Constitutive Androstane Receptor, Pregnane X Receptor, Peroxisome Proliferator-Activated Receptor {alpha}, and Nuclear Factor Erythroid 2-Related Factor 2 Drug Metab. Dispos., April 1, 2009; 37(4): 847 - 856. [Abstract] [Full Text] [PDF]

				U. A. Argikar and R. P. Remmel Effect of Aging on Glucuronidation of Valproic Acid in Human Liver Microsomes and the Role of UDP-Glucuronosyltransferase UGT1A4, UGT1A8, and UGT1A10 Drug Metab. Dispos., January 1, 2009; 37(1): 229 - 236. [Abstract] [Full Text] [PDF]

				P. B. Pennell, L. Peng, D. J. Newport, J. C. Ritchie, A. Koganti, D. K. Holley, M. Newman, and Z. N. Stowe Lamotrigine in pregnancy: Clearance, therapeutic drug monitoring, and seizure frequency Neurology, May 27, 2008; 70(22_Part_2): 2130 - 2136. [Abstract] [Full Text] [PDF]

				N. Nguyen, J. A. Bonzo, S. Chen, S. Chouinard, M. J. Kelner, G. Hardiman, A. Belanger, and R. H. Tukey Disruption of the Ugt1 Locus in Mice Resembles Human Crigler-Najjar Type I Disease J. Biol. Chem., March 21, 2008; 283(12): 7901 - 7911. [Abstract] [Full Text] [PDF]

				D. Zhang, D. Zhang, D. Cui, J. Gambardella, L. Ma, A. Barros, L. Wang, Y. Fu, S. Rahematpura, J. Nielsen, et al. Characterization of the UDP Glucuronosyltransferase Activity of Human Liver Microsomes Genotyped for the UGT1A1*28 Polymorphism Drug Metab. Dispos., December 1, 2007; 35(12): 2270 - 2280. [Abstract] [Full Text] [PDF]

				M.-F. Yueh and R. H. Tukey Nrf2-Keap1 Signaling Pathway Regulates Human UGT1A1 Expression in Vitro and in Transgenic UGT1 Mice J. Biol. Chem., March 23, 2007; 282(12): 8749 - 8758. [Abstract] [Full Text] [PDF]

				K. Senekeo-Effenberger, S. Chen, E. Brace-Sinnokrak, J. A. Bonzo, M.-F. Yueh, U. Argikar, J. Kaeding, J. Trottier, R. P. Remmel, J. K. Ritter, et al. Expression of the Human UGT1 Locus in Transgenic Mice by 4-Chloro-6-(2,3-xylidino)-2-pyrimidinylthioacetic Acid (WY-14643) and Implications on Drug Metabolism through Peroxisome Proliferator-Activated Receptor {alpha} Activation Drug Metab. Dispos., March 1, 2007; 35(3): 419 - 427. [Abstract] [Full Text] [PDF]

				D. B. Buckley and C. D. Klaassen Tissue- and Gender-Specific mRNA Expression of UDP-Glucuronosyltransferases (UGTs) in Mice Drug Metab. Dispos., January 1, 2007; 35(1): 121 - 127. [Abstract] [Full Text] [PDF]

				T. N. Operana, N. Nguyen, S. Chen, D. Beaton, and R. H. Tukey Human CYP1A1GFP Expression in Transgenic Mice Serves as a Biomarker for Environmental Toxicant Exposure Toxicol. Sci., January 1, 2007; 95(1): 98 - 107. [Abstract] [Full Text] [PDF]