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Journal of Lipid Research, Vol. 45, 1694-1703, September 2004
Copyright © 2004 by American Society for Biochemistry and Molecular Biology

Glucuronidation of oxidized fatty acids and prostaglandins B₁ and E₂ by human hepatic and recombinant UDP-glucuronosyltransferases

Joanna M. Little^*, Mika Kurkela, Julia Sonka^*, Sirkku Jäntti, Raimo Ketola, Stacie Bratton^*, Moshe Finel and Anna Radominska-Pandya^1,*

^* Department of Biochemistry and Molecular Biology, University of Arkansas for Medical Sciences, Little Rock, AR
Viikki Drug Discovery Technology Center, Faculty of Pharmacy, University of Helsinki, Helsinki, Finland

¹ To whom correspondence should be addressed. e-mail: radominskaanna{at}uams.edu

Arachidonic acid (AA) can be metabolized to various metabolites, which can act as mediators of cellular processes. The objective of this work was to identify whether AA, prostaglandin (PG) B₁ and E₂, and 15- and 20-hydroxyeicosatetraenoic acids (15- and 20-HETE) are metabolized via glucuronidation. Assays with human recombinant UDP-glucuronosyltransferase 1A (UGT1A) isoforms revealed that AA and 15-HETE were glucuronidated by UGT1A1, 1A3, 1A4, 1A9, and 1A10, whereas 20-HETE was glucuronidated by UGT1A1 and 1A4 and PGB₁ was glucuronidated by UGT1A1, 1A9, and 1A10. All substrates were glucuronidated by recombinant UGT2B7, with AA and 20-HETE being the best substrates. Kinetic analysis of UGT1A1 and 1A9 with AA resulted in K_m values of 37.9 and 45.8 µM, respectively. PGB₁ was glucuronidated by UGT1A1 with a K_m of 26.3 µM. The K_m values for all substrates with UGT2B7 were significantly higher than with the UGT1A isoforms. Liquid chromatography-mass spectrometry of glucuronides biosynthesized from PGB₁ and 15-HETE showed that hydroxyl groups were the major target of glucuronidation.

This work demonstrates a novel metabolic pathway for HETEs and PGs and the role of UGT1A isoforms in this process. These results indicate that glucuronidation may play a significant role in modulation of the availability of these fatty acid derivatives for cellular processes.

Abbreviations: AA, arachidonic acid; GlcUA, glucuronic acid; HETE, hydroxyeicosatetraenoic acid; HI, human intestine; HL, human liver; 13-HODE, 13-hydroxyoctadecadienoic acid; LA, linoleic acid; LC-MS, liquid chromatography-mass spectrometry; OFA, oxidized fatty acid; 13-OXO, 13-oxooctadecadienoic acid; PG, prostaglandin; UDP-GlcUA, UDP-glucuronic acid; UGT, UDP-glucuronosyltransferase

Supplementary key words uridine diphosphate-glucuronosyltransferase • prostaglandins • hydroxyeicosatetraenoic acid • human liver • human intestine • liquid chromatography-mass spectrometry

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