J. Lipid Res.
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A more recent version of this article appeared on September 1, 2004

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J. Lipid Res., doi:10.1194/jlr.M400103-JLR200
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Submitted on March 15, 2004
Revised on June 16, 2004
Accepted on June 18, 2004

Glucuronidation of oxidized fatty acids and prostaglandins B1 and E2 by human hepatic and recombinant udpglucuronosyltransferases (UGT)

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

Department of Biochemistry and Molecular Biology, University of Arkansas for Med Sciences, Little Rock, AR 72205

Corresponding Author: 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, prostaglandins PGB1 and PGE2, and 15- and 20-hydroxyeicosatetraenoic acids (15- and 20-HETE) are metabolized via glucuronidation. Assays with human recombinant 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 Kms of 37.7 and 45.8 mu M, respectively. PGB1 was glucuronidated by UGT1A1 with a Kmof 26.3 mu M. The Kms for all substrates with UGT2B7 were significantly higher than with the UGT1A isoforms. LC-MS 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 ther 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.


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