Regulation of the human bilirubin UDP-glucuronosyltransferase gene

Brierley, Catherine H.; Senafi, Sahidan; Clarke, D.W.; Hsu, Mei Hui; Johnson, Eric F.; Burchell, Brian

doi:10.1016/0065-2571(95)00006-2

Cited by 32 publications

(28 citation statements)

References 23 publications

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“…Phenobarbital (PB) is one of the best-known modulators because of its therapeutic use in patients with CNS type II and Gilbert's syndrome due to its ability to increase bilirubin-conjugating activity [15]. PB has been reported to induce UGT1A1-dependent bilirubin conjugation, mRNA expression, and/or protein expression in both human liver and primary human hepatocytes 1.3-to 3.8-fold in various studies [16][17][18]. Microsomes isolated from the livers of subjects with a history of phenytoin therapy exhibited 3-fold and 2.2-fold increases in UGT1A1 mRNA level and bilirubin activity, respectively [17,18].…”

Section: Introductionmentioning

confidence: 99%

Modulation of UDP‐glucuronosyltransferase 1A1 in primary human hepatocytes by prototypical inducers

Smith

Faucette

Wang

et al. 2005

J Biochem & Molecular Tox

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The primary objective of this study was to evaluate the modulation of UGT1A1 expression in human hepatocytes using prototypical CYP450 inducers. A bank of 16 human livers was utilized to obtain an estimate of the range of UGT1A1 protein expression and catalytic activity. Concentration-dependent changes in UGT1A1 response were evaluated in hepatocyte cultures after treatment with 3-methylchloranthrene, beta-napthoflavone, rifampicin, or phenobarbital. Pharmacodynamic analyses of UGT1A1 expression were conducted and compared to those of CYP450 after treatment with inducers in 2-3 different hepatocyte preparations. Additionally, expression of UGT1A1 mRNA and protein was evaluated in human hepatocytes treated with 14 different compounds known to activate differentially the human pregnane-X-receptor or constitutive androstane receptor. Pharmacodynamic modeling revealed EC50 values statistically significant between UGT1A1 and CYP2B6 after treatment with PB, but not statistically distinguishable between UGT1A1 and CYP's 1A2 or 3A4 after treatment with 3-methylchloranthrene or rifampicin, respectively. UGT1A1 was most responsive to the pregnane-X-receptor-agonists rifampicin, ritonavir, and clotrimazole at the mRNA level and, to a lesser extent, the constitutive androstane receptor-activators, phenobarbital and phenytoin. Pharmacodynamic analyses support a mechanism of coordinate regulation between UGT1A1 and a number of CYP450 enzymes by multiple nuclear receptors.

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Section: Introductionmentioning

confidence: 99%

Modulation of UDP‐glucuronosyltransferase 1A1 in primary human hepatocytes by prototypical inducers

Smith

Faucette

Wang

et al. 2005

J Biochem & Molecular Tox

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“…Both the human UGT1A1 and UGT1A6 genes utilize TATA boxes to initiate transcription (12,26). However, initiation of gene transcription by RNA polymerase II may also occur through initiator regions in the promoters of genes.…”

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confidence: 99%

Cloning and Characterization of the Human UDP-glucuronosyltransferase 1A8, 1A9, and 1A10 Gene Promoters

Gregory¹,

Gardner-Stephen²,

Lewinsky

et al. 2003

Journal of Biological Chemistry

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The human UDP-glucuronosyltransferases, UGT1A8, 1A9, and 1A10, are closely related in sequence and have a major role in the elimination of lipophilic chemicals by glucuronidation. UGT1A8 and 1A10 are expressed exclusively in the gastrointestinal tract, whereas UGT1A9 is expressed mainly in the liver and kidneys. To determine the factors contributing to the extrahepatic expression of these UDP-glucuronosyltransferases, we have cloned and characterized the promoters of the UGT1A8, 1A9, and 1A10 genes and studied their regulation in the colon cell line, Caco2. Their transcription start sites were mapped, and a functional overlapping Sp1/initiator-like site was identified which strongly contributed to UGT1A8 and 1A10 promoter activity. The high promoter activity of UGT1A8 and 1A10 correlated with the binding of nuclear proteins (complex B) to this region. Two-bp differences in the corresponding site in the UGT1A9 promoter prevented the binding of complex B and reduced promoter activity. Although Sp1 was able to bind to the Sp1/initiator-like site, its binding was dispensable for promoter activity. However, the binding of Sp1 to a second Sp1 site 30 bp 5 to the Sp1/initiatorlike site greatly enhanced the activity of the UGT1A8 and 1A10 promoters. These results provide evidence that the UGT1A8, 1A9, and 1A10 genes are differentially regulated through an initiator element in their 5-flanking regions.

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“…Three-to 4-fold induction of UGT1A1, at best, has been observed in our laboratory and those of others using prototypical inducing agents in primary human hepatocytes (HH) (Sutherland et al, 1993;Brierley et al, 1996;Ritter et al, 1999;Soars et al, 2004;Smith et al, 2005). As such, the large UGT1A1 induction response observed in immortalized cell lines after chrysin exposure seems rather atypical.…”

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confidence: 78%

Differential UGT1A1 Induction by Chrysin in Primary Human Hepatocytes and HepG2 Cells

Smith¹,

Graham²,

Król³

et al. 2005

J Pharmacol Exp Ther

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Chrysin, a dietary flavonoid, has been shown to markedly induce UGT1A1 expression and activity in HepG2 and Caco-2 cell lines; thus, it has been suggested to have clinical utility in the treatment of UGT1A1-mediated deficiencies, such as unconjugated hyperbilirubinemia or the prevention of 7-ethyl-10-hydroxycamptothecin (SN-38) toxicity. However, little is known about its induction potential in a more physiologically relevant model system, such as primary hepatocyte culture. In this study, induction of UGT1A1 expression (mRNA, protein, and activity) was investigated in primary human hepatocyte cultures after treatment with chrysin and other prototypical inducers. Endogenous nuclear receptor-mediated UGT1A1 induction was studied using transient transfection reporter assays in primary human hepatocytes and HepG2 cells. Results indicated that induction of UGT1A1 expression was minimal in human hepatocytes treated with chrysin compared with that in HepG2 cells (1.2-versus 11-fold, respectively). Subsequent experiments to determine whether the differential response was due to its metabolic stability revealed strikingly different elimination rate constants between the two cell systems (half-life of 13 min in human hepatocytes versus 122 min in HepG2 cell suspensions). Further study demonstrated that UGT1A1 mRNA expression could be induced in human hepatocyte cultures by either increasing the chrysin dosing frequency or by modulating chrysin metabolism, suggesting that the differential induction observed in hepatocytes and HepG2 cells was due to differences in the metabolic clearance of chrysin. In conclusion, this study suggests that the metabolic stability of chrysin likely would limit its ability to induce UGT1A1 in vivo.

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Regulation of the human bilirubin UDP-glucuronosyltransferase gene

Cited by 32 publications

References 23 publications

Modulation of UDP‐glucuronosyltransferase 1A1 in primary human hepatocytes by prototypical inducers

Modulation of UDP‐glucuronosyltransferase 1A1 in primary human hepatocytes by prototypical inducers

Cloning and Characterization of the Human UDP-glucuronosyltransferase 1A8, 1A9, and 1A10 Gene Promoters

Differential UGT1A1 Induction by Chrysin in Primary Human Hepatocytes and HepG2 Cells

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