title: Tissue-specific, inducible, and hormonal control of the human UDP-glucuronosyltransferase-1 (UGT1) locus.
abstract: 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-16alpha-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.
authors.affiliation: Laboratory of Environmental Toxicology, Department of Pharmacology, University of California, San Diego, La Jolla, 92093-0722, USA.
authors.forename: Shujuan
authors.initials: S
authors.lastname: Chen
authors.forename: Deirdre
authors.initials: D
authors.lastname: Beaton
authors.forename: Nghia
authors.initials: N
authors.lastname: Nguyen
authors.forename: Kathy
authors.initials: K
authors.lastname: Senekeo-Effenberger
authors.forename: Erin
authors.initials: E
authors.lastname: Brace-Sinnokrak
authors.forename: Upendra
authors.initials: U
authors.lastname: Argikar
authors.forename: Rory P
authors.initials: RP
authors.lastname: Remmel
authors.forename: Jocelyn
authors.initials: J
authors.lastname: Trottier
authors.forename: Olivier
authors.initials: O
authors.lastname: Barbier
authors.forename: Joseph K
authors.initials: JK
authors.lastname: Ritter
authors.forename: Robert H
authors.initials: RH
authors.lastname: Tukey
mesh_terms: D000818:Animals; D004790:Enzyme Induction / Q000187:drug effects; D005260:Female; D041981:Gastrointestinal Tract / Q000166:cytology / Q000378:metabolism; D020869:Gene Expression Profiling; D005938:Glucocorticoids / Q000378:metabolism / Q000494:pharmacology*; D014453:Glucuronosyltransferase / Q000096:biosynthesis / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D007774:Lactation; D008099:Liver / Q000201:enzymology; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D008861:Microsomes / Q000201:enzymology / Q000378:metabolism; D009928:Organ Specificity; D011247:Pregnancy; D000077297:Pregnane X Receptor; D018336:Receptors, Aryl Hydrocarbon / Q000819:agonists / Q000378:metabolism; D018160:Receptors, Cytoplasmic and Nuclear / Q000819:agonists / Q000378:metabolism; D011987:Receptors, Steroid / Q000819:agonists / Q000378:metabolism
chemical_list: D005938:Glucocorticoids; D000077297:Pregnane X Receptor; D018336:Receptors, Aryl Hydrocarbon; D018160:Receptors, Cytoplasmic and Nuclear; D011987:Receptors, Steroid; D014453:Glucuronosyltransferase