title: An assessment of udp-glucuronosyltransferase induction using primary human hepatocytes.
abstract: Uridine diphosphate glucuronosyltransferases (UGTs) catalyze the glucuronidation of a wide range of xenobiotics and endogenous substrates. However, there is a lack of information concerning the response of human UGTs to inducers, and this observation prompted the current investigation. The glucuronidation of estradiol (3- and 17-positions), naphthol, propofol, and morphine (3- and 6-positions) was assessed against a battery of recombinant human UGTs to determine selective glucuronidation reactions for induction studies. The potential induction of the glucuronidation of estradiol at the 3-position, naphthol, propofol, and morphine at the 3-position was subsequently investigated in cultured primary human hepatocytes against a range of prototypic inducers including dexamethasone, 3-methylcholanthrene (3-MC), phenobarbital, rifampicin, and omeprazole. Treatment with 3-MC induced estradiol-3-glucuronidation (up to 2.5-fold) in four of five donors investigated. Statistically significant increases in naphthol glucuronidation (up to 1.7-fold) were observed following treatment with carbamazepine. UGT1A9-mediated propofol glucuronidation was induced by phenobarbital (up to 2.2-fold) and rifampicin (up to 1.7-fold). However, treatment with alpha-naphthoflavone and tangeretin resulted in a decrease in propofol glucuronidation (30% of control values). Statistically significant induction of morphine-3-glucuronidation was observed in at least three donors following treatment with phenobarbital, rifampicin, and carbamazepine. Each UGT isoform investigated displayed a distinct induction profile. Although statistically significant increases in glucuronidation were observed for each reaction studied, the level of induction was less than that observed for CYP1A2 or CYP3A4 and exhibited a large interdonor variability. The clinical relevance of the induction responses obtained in this study is unclear.
authors.affiliation: Department of Drug Disposition, Lilly Research Laboratories, Drop Code 0710, Eli Lilly and Company, Indianapolis, IN 46285, USA.
authors.forename: Matthew G
authors.initials: MG
authors.lastname: Soars
authors.forename: David M
authors.initials: DM
authors.lastname: Petullo
authors.forename: James A
authors.initials: JA
authors.lastname: Eckstein
authors.forename: Steve C
authors.initials: SC
authors.lastname: Kasper
authors.forename: Steven A
authors.initials: SA
authors.lastname: Wrighton
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D002478:Cells, Cultured; D002648:Child; D002675:Child, Preschool; D002851:Chromatography, High Pressure Liquid; D019363:Cytochrome P-450 CYP1A1 / Q000378:metabolism; D019388:Cytochrome P-450 CYP1A2 / Q000096:biosynthesis; D051544:Cytochrome P-450 CYP3A; D003577:Cytochrome P-450 Enzyme System / Q000096:biosynthesis; D004790:Enzyme Induction / Q000187:drug effects*; D004958:Estradiol / Q000378:metabolism; D005260:Female; D020719:Glucuronides / Q000378:metabolism; D014453:Glucuronosyltransferase / Q000096:biosynthesis*; D022781:Hepatocytes / Q000201:enzymology*; D006801:Humans; D006915:Hydroxytestosterones / Q000378:metabolism; D007527:Isoenzymes / Q000096:biosynthesis; D008297:Male; D013058:Mass Spectrometry; D008875:Middle Aged; D009020:Morphine / Q000378:metabolism; D009284:Naphthols / Q000378:metabolism; D015742:Propofol / Q000378:metabolism; D011994:Recombinant Proteins / Q000096:biosynthesis; D013379:Substrate Specificity
chemical_list: D020719:Glucuronides; D006915:Hydroxytestosterones; D007527:Isoenzymes; D009284:Naphthols; D011994:Recombinant Proteins; D004958:Estradiol; C025591:6 beta-hydroxytestosterone; D009020:Morphine; D003577:Cytochrome P-450 Enzyme System; C104464:CYP3A protein, human; D019363:Cytochrome P-450 CYP1A1; D019388:Cytochrome P-450 CYP1A2; D051544:Cytochrome P-450 CYP3A; C510163:CYP3A4 protein, human; D014453:Glucuronosyltransferase; D015742:Propofol