title: UGT1A10 Is a High Activity and Important Extrahepatic Enzyme: Why Has Its Role in Intestinal Glucuronidation Been Frequently Underestimated?
abstract: The aim of this work was to highlight a considerable and broad problem in UGT1A10 activity assessment that has led to underestimation of its role in intestinal glucuronidation of drugs and other xenobiotics. The reason appears to be poor activity of the commercial UGT1A10 that is used by many laboratories, and here we have tested it by comparison with our recombinant His-tagged UGT1A10 (designated as UGT1A10-H), both expressed in insect cells. The glucuronidation rates of morphine, estradiol, estrone, SN-38, diclofenac, 4-methylumbelliferone, 7-amino-4-methylcoumarin, N-(3-carboxypropyl)-4-hydroxy-1,8-naphthalimide, and bavachinin were assayed. The results revealed that the activity of commercial UGT1A10 was low, very low, and in the cases of morphine, estrone, 7-methyl-4-aminocoumarin, and bavachinin it was below the detection limit. On the other hand, under the same conditions, UGT1A10-H exhibited high glucuronidation rates toward all these compounds. Moreover, using estradiol, morphine, and estrone, in the presence and absence of suitable inhibitors, nilotinib or atractylenolide I, it was demonstrated that UGT1A10-H, but not the commercial UGT1A10, provides a good tool to study the role of native UGT1A10 in the human intestine. The results also suggest that much of the data in the literature on UGT1A10 activity may have to be re-evaluated.
authors.affiliation: Division of Pharmaceutical Chemistry and Technology, Faculty of Pharmacy, University of Helsinki , Finland.
authors.forename: Johanna
authors.initials: J
authors.lastname: Troberg
authors.affiliation: Division of Pharmaceutical Chemistry and Technology, Faculty of Pharmacy, University of Helsinki , Finland.
authors.forename: Erkka
authors.initials: E
authors.lastname: Järvinen
authors.affiliation: Laboratory of Pharmaceutical Resource Discovery, Dalian Institute of Chemical Physics, Chinese Academy of Sciences , Dalian, 116023, China.
authors.forename: Guang-Bo
authors.initials: GB
authors.lastname: Ge
authors.affiliation: Laboratory of Pharmaceutical Resource Discovery, Dalian Institute of Chemical Physics, Chinese Academy of Sciences , Dalian, 116023, China.
authors.forename: Ling
authors.initials: L
authors.lastname: Yang
authors.affiliation: Division of Pharmaceutical Chemistry and Technology, Faculty of Pharmacy, University of Helsinki , Finland.
authors.forename: Moshe
authors.identifier: 0000-0003-1775-854X
authors.initials: M
authors.lastname: Finel
mesh_terms: D000818:Animals; D015153:Blotting, Western; D002166:Camptothecin / Q000031:analogs & derivatives / Q000378:metabolism; D002851:Chromatography, High Pressure Liquid; D003374:Coumarins / Q000378:metabolism; D004008:Diclofenac / Q000378:metabolism; D004958:Estradiol / Q000378:metabolism; D004970:Estrone / Q000378:metabolism; D005419:Flavonoids / Q000378:metabolism; D014453:Glucuronosyltransferase / Q000378:metabolism*; D006801:Humans; D006923:Hymecromone / Q000378:metabolism; D007413:Intestinal Mucosa / Q000378:metabolism*; D000077146:Irinotecan; D007700:Kinetics; D008862:Microsomes, Liver / Q000378:metabolism; D047309:Flavones
chemical_list: D002166:Camptothecin; D003374:Coumarins; D004008:Diclofenac; D004958:Estradiol; D004970:Estrone; D005419:Flavonoids; D014453:Glucuronosyltransferase; D006923:Hymecromone; D000077146:Irinotecan; C476725:bilirubin uridine-diphosphoglucuronosyl transferase 1A10; C028743:7-amino-4-methylcoumarin; C468752:bavachinin; D047309:Flavones
keywords: AMC; NCHN; SN-38; UDP-glucuronosyltransferase; bavachinin; estradiol; estrone; intestinal glucuronidation; intestine microsomes; morphine; recombinant UGT1A10