title: Determination of major UDP-glucuronosyltransferase enzymes and their genotypes responsible for 20-HETE glucuronidation.
abstract: The compound 20-HETE is involved in numerous physiological functions, including blood pressure and platelet aggregation. Glucuronidation of 20-HETE by UDP-glucuronosyltransferases (UGTs) is thought to be a primary pathway of 20-HETE elimination in humans. The present study identified major UGT enzymes responsible for 20-HETE glucuronidation and investigated their genetic influence on the glucuronidation reaction using human livers (n = 44). Twelve recombinant UGTs were screened to identify major contributors to 20-HETE glucuronidation. Based on these results, UGT2B7, UGT1A9, and UGT1A3 exhibited as major contributors to 20-HETE glucuronidation. The Km values of 20-HETE glucuronidation by UGT1A3, UGT1A9, and UGT2B7 were 78.4, 22.2, and 14.8 μM, respectively, while Vmax values were 1.33, 1.78, and 1.62 nmol/min/mg protein, respectively. Protein expression levels and genetic variants of UGT1A3, UGT1A9, and UGT2B7 were analyzed in human livers using Western blotting and genotyping, respectively. Glucuronidation of 20-HETE was significantly correlated with the protein levels of UGT2B7 (r(2) = 0.33, P < 0.001) and UGT1A9 (r(2) = 0.31, P < 0.001), but not UGT1A3 (r(2) = 0.02, P > 0.05). A correlation between genotype and 20-HETE glucuronidation revealed that UGT2B7 802C>T, UGT1A9 -118T9>T10, and UGT1A9 1399T>C significantly altered 20-HETE glucuronide formation (P < 0.05-0.001). Increased levels of 20-HETE comprise a risk factor for cardiovascular diseases, and the present data may increase our understanding of 20-HETE metabolism and cardiovascular complications.
authors.affiliation: Department of Pharmacology and PharmacoGenomics Research Center Inje University College of Medicine, Busan, South Korea.
authors.forename: Yazun Bashir
authors.initials: YB
authors.lastname: Jarrar
authors.affiliation: Department of Pharmacology and PharmacoGenomics Research Center Inje University College of Medicine, Busan, South Korea.
authors.forename: Eun-Young
authors.initials: EY
authors.lastname: Cha
authors.affiliation: Department of Pharmacology and PharmacoGenomics Research Center Inje University College of Medicine, Busan, South Korea.
authors.forename: Kyung-Ah
authors.initials: KA
authors.lastname: Seo
authors.affiliation: Department of Pharmacology and PharmacoGenomics Research Center Inje University College of Medicine, Busan, South Korea Department of Clinical Pharmacology, Inje University College of Medicine, Busan, South Korea.
authors.forename: Jong-Lyul
authors.initials: JL
authors.lastname: Ghim
authors.affiliation: Department of Pharmacology and PharmacoGenomics Research Center Inje University College of Medicine, Busan, South Korea.
authors.forename: Hyo-Ji
authors.initials: HJ
authors.lastname: Kim
authors.affiliation: Department of Pharmacology and PharmacoGenomics Research Center Inje University College of Medicine, Busan, South Korea.
authors.forename: Dong-Hyun
authors.initials: DH
authors.lastname: Kim
authors.affiliation: Department of Pharmacology and PharmacoGenomics Research Center Inje University College of Medicine, Busan, South Korea.
authors.forename: Su-Jun
authors.initials: SJ
authors.lastname: Lee
authors.affiliation: Department of Pharmacology and PharmacoGenomics Research Center Inje University College of Medicine, Busan, South Korea Department of Clinical Pharmacology, Inje University College of Medicine, Busan, South Korea.
authors.forename: Jae-Gook
authors.initials: JG
authors.lastname: Shin
mesh_terms: D000328:Adult; D014644:Genetic Variation; D005838:Genotype; D020723:Glucuronic Acid / Q000378:metabolism*; D014453:Glucuronosyltransferase / Q000235:genetics* / Q000378:metabolism*; D006801:Humans; D006893:Hydroxyeicosatetraenoic Acids / Q000378:metabolism*; D007527:Isoenzymes / Q000235:genetics / Q000378:metabolism; D007700:Kinetics; D008862:Microsomes, Liver / Q000378:metabolism
chemical_list: D006893:Hydroxyeicosatetraenoic Acids; D007527:Isoenzymes; C055987:20-hydroxy-5,8,11,14-eicosatetraenoic acid; D020723:Glucuronic Acid; D014453:Glucuronosyltransferase
keywords: 20-hydroxyeicosatetraenoic acid; arachidonic acid; genetic polymorphisms; uridine diphosphate-glucuronosyltransferase