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, Olivier Barbier, Joseph K. Ritter, Robert H. Tukey

Research output: Contribution to journalArticle

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Abstract

The human UDP-glucuronosyitransferase 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-16α-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-UGT1 mice, 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.

Original languageEnglish (US)
Pages (from-to)37547-37557
Number of pages11
JournalJournal of Biological Chemistry
Volume280
Issue number45
DOIs
StatePublished - Nov 11 2005

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Glucuronosyltransferase
Pregnenolone Carbonitrile
Transgenic Mice
Liver
Tissue
Xenobiotics
Metabolism
Mothers
Genes
Lithocholic Acid
Chenodeoxycholic Acid
Proteins
Ethinyl Estradiol
Uridine Diphosphate
Nursing
Parturition
Chromosomes
Aryl Hydrocarbon Receptors
Gene expression
Chromosomes, Human, Pair 2

Cite this

Chen, S., Beaton, D., Nguyen, N., Senekeo-Effenberger, K., Brace-Sinnokrak, E., Argikar, U., ... Tukey, R. H. (2005). Tissue-specific, inducible, and hormonal control of the human UDP-glucuronosyltransferase-1 (UGT1) locus. Journal of Biological Chemistry, 280(45), 37547-37557. https://doi.org/10.1074/jbc.M506683200

Tissue-specific, inducible, and hormonal control of the human UDP-glucuronosyltransferase-1 (UGT1) locus. / Chen, Shujuan; Beaton, Deirdre; Nguyen, Nghia; Senekeo-Effenberger, Kathy; Brace-Sinnokrak, Erin; Argikar, Upendra; Remmel, Rory P; Trottier, Jocelyn; Barbier, Olivier; Ritter, Joseph K.; Tukey, Robert H.

In: Journal of Biological Chemistry, Vol. 280, No. 45, 11.11.2005, p. 37547-37557.

Research output: Contribution to journalArticle

Chen, S, Beaton, D, Nguyen, N, Senekeo-Effenberger, K, Brace-Sinnokrak, E, Argikar, U, Remmel, RP, Trottier, J, Barbier, O, Ritter, JK & Tukey, RH 2005, 'Tissue-specific, inducible, and hormonal control of the human UDP-glucuronosyltransferase-1 (UGT1) locus', Journal of Biological Chemistry, vol. 280, no. 45, pp. 37547-37557. https://doi.org/10.1074/jbc.M506683200
Chen S, Beaton D, Nguyen N, Senekeo-Effenberger K, Brace-Sinnokrak E, Argikar U et al. Tissue-specific, inducible, and hormonal control of the human UDP-glucuronosyltransferase-1 (UGT1) locus. Journal of Biological Chemistry. 2005 Nov 11;280(45):37547-37557. https://doi.org/10.1074/jbc.M506683200
Chen, Shujuan ; Beaton, Deirdre ; Nguyen, Nghia ; Senekeo-Effenberger, Kathy ; Brace-Sinnokrak, Erin ; Argikar, Upendra ; Remmel, Rory P ; Trottier, Jocelyn ; Barbier, Olivier ; Ritter, Joseph K. ; Tukey, Robert H. / Tissue-specific, inducible, and hormonal control of the human UDP-glucuronosyltransferase-1 (UGT1) locus. In: Journal of Biological Chemistry. 2005 ; Vol. 280, No. 45. pp. 37547-37557.
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