title: Glucuronidation of carboxylic acid containing compounds by UDP-glucuronosyltransferase isoforms.
abstract: Glucuronide conjugation of xenobiotics containing a carboxylic acid moiety represents an important metabolic pathway for these compounds in humans. Several human UDP-glucuronosyltransferases (UGTs) have been shown to catalyze the formation of acyl-glucuronides, including UGT2B7, UGT1A3, and UGT1A9. In this study, recombinant expressed UGT isoforms were investigated with many structurally related carboxylic acid analogues, and the UGT rank order for catalyzing the glucuronidation of carboxylic acids was UGT2B7?UGT1A3 approximately UGT1A9. Despite being a poor substrate with UGT1A3, coumarin-3-carboxylic acid was not a substrate for any other UGT isoform tested in this study, suggesting that it could be a specific substrate for UGT1A3. Interestingly, UGT1A7 and UGT1A10 also react with several carboxylic acid aglycones. Kinetic analysis showed that UGT2B7 exhibits much higher glucuronidation efficiency (Vmax/Km) with ibuprofen, ketoprofen, and others, compared to UGT1A3. These data indicate that UGT2B7 could be the major isoform involved in the glucuronidation of carboxylic acid compounds in humans.
authors.affiliation: Merck Research Laboratories, San Diego, 3535 General Atomics Court, San Diego, CA 92121, USA.
authors.forename: Kayo
authors.initials: K
authors.lastname: Sakaguchi
authors.forename: Mitchell
authors.initials: M
authors.lastname: Green
authors.forename: Nicholas
authors.initials: N
authors.lastname: Stock
authors.forename: Thomas S
authors.initials: TS
authors.lastname: Reger
authors.forename: Jasmine
authors.initials: J
authors.lastname: Zunic
authors.forename: Christopher
authors.initials: C
authors.lastname: King
mesh_terms: D002264:Carboxylic Acids; D002460:Cell Line; D004789:Enzyme Activation; D020719:Glucuronides / Q000737:chemistry*; D014453:Glucuronosyltransferase / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D006801:Humans; D007527:Isoenzymes / Q000737:chemistry; D007668:Kidney / Q000196:embryology / Q000201:enzymology*; D011994:Recombinant Proteins / Q000096:biosynthesis / Q000737:chemistry; D013329:Structure-Activity Relationship; D013777:Tetrazoles / Q000737:chemistry*; D000090264:UDP-Glucuronosyltransferase 1A9
chemical_list: D002264:Carboxylic Acids; D020719:Glucuronides; D007527:Isoenzymes; D011994:Recombinant Proteins; D013777:Tetrazoles; C000715591:UGT1A9 protein, human; C122075:UDP-glucuronosyltransferase, UGT1A3; C491474:UGT2B7 protein, human; D014453:Glucuronosyltransferase; D000090264:UDP-Glucuronosyltransferase 1A9