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J. Lipid Res.
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Originally published In Press as doi:10.1194/jlr.M400510-JLR200 on February 16, 2005

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Journal of Lipid Research, Vol. 46, 1001-1008, May 2005
Copyright © 2005 by American Society for Biochemistry and Molecular Biology

Evidence for two enzymatic pathways for {omega}-oxidation of docosanoic acid in rat liver microsomes

Robert-Jan Sanders, Rob Ofman, Fredoen Valianpour, Stephan Kemp and Ronald J. A. Wanders1

Academic Medical Center, University of Amsterdam, Laboratory Genetic Metabolic Diseases, Departments of Pediatrics/Emma Children's Hospital and Clinical Chemistry, 1105 AZ Amsterdam, The Netherlands

1 To whom correspondence should be addressed. e-mail: r.j.wanders{at}amc.uva.nl

We studied the {omega}-oxidation of docosanoic acid (C22:0) in rat liver microsomes. C22:0 and 22-hydroxy-docosanoic acid ({omega}-hydroxy-C22:0) were used as substrates, and the reaction products were analyzed by electrospray ionization mass spectrometry. In the presence of NADPH, {omega}-oxidation of C22:0 produced not only the hydroxylated product, {omega}-hydroxy-C22:0, but also the dicarboxylic acid of C22:0, docosanedioic acid (C22:0-DCA). When rat liver microsomes were incubated with {omega}-hydroxy-C22:0 in the presence of either NAD+ or NADPH, C22:0-DCA was formed readily. Formation of C22:0-DCA from either C22:0 or {omega}-hydroxy-C22:0 with NADPH as cofactor was inhibited strongly by miconazole and disulfiram, whereas no inhibition was found with NAD+ as cofactor. Furthermore, {omega}-oxidation of C22:0 was reduced significantly when molecular oxygen was depleted. The high sensitivity toward the more specific cytochrome P450 inhibitors ketoconazole and 17-octadecynoic acid suggests that hydroxylation of C22:0 and {omega}-hydroxy-C22:0 may be catalyzed by one or more cytochrome P450 hydroxylases belonging to the CYP4A and/or CYP4F subfamily.

This study demonstrates that C22:0 is a substrate for the {omega}-oxidation system in rat liver microsomes and that the product of the first hydroxylation step, {omega}-hydroxy-C22:0, may undergo further oxidation via two distinct pathways driven by NAD+ or NADPH.

Abbreviations: C22:0, docosanoic acid; C22:0-DCA, docosanedioic acid; {omega}-hydroxy-C22:0, 22-hydroxy-docosanoic acid; 17-ODYA, 17-octadecynoic acid; VLCFA, very long-chain fatty acid

Supplementary key words hydroxylase • cytochrome P450 • {omega}-hydroxy-fatty acids • dicarboxylic acids


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