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.
Highlights
The UGT1A gene products are generated by a strategy of exon sharing, resulting in a family of microsomal proteins in which each contains a divergent amino-terminal 280 amino acids and a commonly shared carboxyl terminus that encodes 245 amino acids (7, 8)
Glucocorticoids work in a synergistic fashion to promote pregnenolone X receptor (PXR) and constitutive androstane receptor induction of the UGT1A1 gene (19), providing support for the theory that circulating hormones may play a crucial role in maintaining appropriate levels pane-1,3-diol; MOPS, 4-morpholinepropanesulfonic acid; CDCA, chenodeoxycholic acid; LCA, lithocholic acid; RT, reverse transcription; TCPOBOP, 1,4-bis-[2-(3,5-dichloropyridyloxy)]benzene; HPLC, high pressure liquid chromatography; WT, wild type; XREs, xenobiotic receptor elements
The copy number of the UDP-glucuronosyltransferase 1 (UGT1) locus in each of these founders was calculated to be ϳ2 (Tg-UGT1a), 1 (Tg-UGT1b), 6 (Tg-UGT1c), 4 (TgUGT1d), and 5 (Tg-UGT1e), the integration of such a large fragment of DNA, often in multiple copies, did not affect fertility, and upon gross pathological examination they were indistinguishable from wild type litter mates
Summary
The UGT1A gene products are generated by a strategy of exon sharing, resulting in a family of microsomal proteins in which each contains a divergent amino-terminal 280 amino acids and a commonly shared carboxyl terminus that encodes 245 amino acids (7, 8). A viable animal model to investigate the in vivo events associated with regulation of the UGT1 locus would promote a better understanding of the role of selective xenobiotic receptors on gene control. Expression of the UGT1 locus in transgenic mice provides a unique opportunity to examine the regulatory properties that control the tissue-specific and xenobiotic receptor-elicited expression patterns of the individual UGT1A genes and enriches an understanding of how the UGT1 locus may be regulated at times where changes are apparent in the physiological levels of circulating hormones. Our results illustrate that the transgenic UGT1 mice will allow for investigation of gene control and protein expression and may advance our understanding of how this locus is regulated in humans
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