title: Modulation of UDP-glucuronosyltransferase 1A1 in primary human hepatocytes by prototypical inducers.
abstract: 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.
authors.affiliation: Division of Drug Delivery and Disposition, School of Pharmacy, CB7360, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
authors.forename: Cornelia M
authors.initials: CM
authors.lastname: Smith
authors.forename: Stephanie R
authors.initials: SR
authors.lastname: Faucette
authors.forename: Hongbing
authors.initials: H
authors.lastname: Wang
authors.forename: Edward L
authors.initials: EL
authors.lastname: LeCluyse
mesh_terms: D002478:Cells, Cultured; D003577:Cytochrome P-450 Enzyme System / Q000096:biosynthesis; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects*; D014453:Glucuronosyltransferase / Q000096:biosynthesis*; D022781:Hepatocytes / Q000378:metabolism*; D006801:Humans; D011083:Polycyclic Compounds / Q000494:pharmacology*; D018160:Receptors, Cytoplasmic and Nuclear / Q000378:metabolism; D000099148:UGT1A1 Enzyme
chemical_list: D003577:Cytochrome P-450 Enzyme System; D014453:Glucuronosyltransferase; D011083:Polycyclic Compounds; D018160:Receptors, Cytoplasmic and Nuclear; D000099148:UGT1A1 Enzyme