An assessment of udp-glucuronosyltransferase induction using primary human hepatocytes

• Published in: Drug metabolism and disposition Vol. 32; no. 1; pp. 140 - 148
• Main Authors: SOARS, Matthew G, PETULLO, David M, ECKSTEIN, James A, KASPER, Steve C, WRIGHTON, Steven A
• Format: Journal Article
• Language: English
• Published: Bethesda, MD American Society for Pharmacology and Experimental Therapeutics 2004
• Subjects: Adolescent; Adult; Aged; Analytical, structural and metabolic biochemistry; Biological and medical sciences; Cells, Cultured; Child; Child, Preschool; Chromatography, High Pressure Liquid; Cytochrome P-450 CYP1A1 - metabolism; Cytochrome P-450 CYP1A2 - biosynthesis; Cytochrome P-450 CYP3A; Cytochrome P-450 Enzyme System - biosynthesis; Enzyme Induction - drug effects; Enzymes and enzyme inhibitors; Estradiol - metabolism; Female; Fundamental and applied biological sciences. Psychology; Glucuronides - metabolism; Glucuronosyltransferase - biosynthesis; Hepatocytes - enzymology; Humans; Hydroxytestosterones - metabolism; Isoenzymes - biosynthesis; Male; Mass Spectrometry; Middle Aged; Morphine - metabolism; Naphthols - metabolism; Propofol - metabolism; Recombinant Proteins - biosynthesis; Substrate Specificity; Transferases; Human; Enzyme inducer; UDP-glucuronosyltransferase; Digestive system; Enzyme; Liver; Transferases; Glycosyltransferases; Glucuronic acid conjugation; In vitro; Hepatocyte; Substrate specificity; Hexosyltransferases
• ISSN: 0090-9556; 1521-009X
• DOI: 10.1124/dmd.32.1.140

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.