HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS		QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

This Article Full Text Full Text (PDF) All Versions of this Article: M400510-JLR200v1 46/5/1001    most recent Alert me when this article is cited Alert me if a correction is posted Citation Map Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Sanders, R.-J. Articles by Wanders, R. J. A. Search for Related Content PubMed PubMed Citation Articles by Sanders, R.-J. Articles by Wanders, R. J. A. Social Bookmarking                      What's this?

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 -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 -oxidation of docosanoic acid (C22:0) in rat liver microsomes. C22:0 and 22-hydroxy-docosanoic acid (-hydroxy-C22:0) were used as substrates, and the reaction products were analyzed by electrospray ionization mass spectrometry. In the presence of NADPH, -oxidation of C22:0 produced not only the hydroxylated product, -hydroxy-C22:0, but also the dicarboxylic acid of C22:0, docosanedioic acid (C22:0-DCA). When rat liver microsomes were incubated with -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 -hydroxy-C22:0 with NADPH as cofactor was inhibited strongly by miconazole and disulfiram, whereas no inhibition was found with NAD⁺ as cofactor. Furthermore, -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 -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 -oxidation system in rat liver microsomes and that the product of the first hydroxylation step, -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; -hydroxy-C22:0, 22-hydroxy-docosanoic acid; 17-ODYA, 17-octadecynoic acid; VLCFA, very long-chain fatty acid

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

CiteULike    Complore    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this?

This article has been cited by other articles:

				R.-J. Sanders, R. Ofman, G. Dacremont, R. J. A. Wanders, and S. Kemp Characterization of the human {omega}-oxidation pathway for {omega}-hydroxy-very-long-chain fatty acids FASEB J, June 1, 2008; 22(6): 2064 - 2071. [Abstract] [Full Text] [PDF]

				S. Leekumjorn, Y. Wu, A. K. Sum, and C. Chan Experimental and Computational Studies Investigating Trehalose Protection of HepG2 Cells from Palmitate-Induced Toxicity Biophys. J., April 1, 2008; 94(7): 2869 - 2883. [Abstract] [Full Text] [PDF]

				H.-Q. Yin, M. Kim, J.-H. Kim, G. Kong, M.-O. Lee, K.-S. Kang, B.-I. Yoon, H.-L. Kim, and B.-H. Lee Hepatic Gene Expression Profiling and Lipid Homeostasis in Mice Exposed to Steatogenic Drug, Tetracycline Toxicol. Sci., November 1, 2006; 94(1): 206 - 216. [Abstract] [Full Text] [PDF]

				F. Xu, V. Y. Ng, D. L. Kroetz, and P. R. O. de Montellano CYP4 Isoform Specificity in the {omega}-Hydroxylation of Phytanic Acid, a Potential Route to Elimination of the Causative Agent of Refsum's Disease J. Pharmacol. Exp. Ther., August 1, 2006; 318(2): 835 - 839. [Abstract] [Full Text] [PDF]

				R.-J. Sanders, R. Ofman, M. Duran, S. Kemp, and R. J. A. Wanders {omega}-Oxidation of Very Long-chain Fatty Acids in Human Liver Microsomes: IMPLICATIONS FOR X-LINKED ADRENOLEUKODYSTROPHY J. Biol. Chem., May 12, 2006; 281(19): 13180 - 13187. [Abstract] [Full Text] [PDF]

				M. A. McDonough, K. L. Kavanagh, D. Butler, T. Searls, U. Oppermann, and C. J. Schofield Structure of Human Phytanoyl-CoA 2-Hydroxylase Identifies Molecular Mechanisms of Refsum Disease J. Biol. Chem., December 9, 2005; 280(49): 41101 - 41110. [Abstract] [Full Text] [PDF]

				M. A. K. Westin, M. C. Hunt, and S. E. H. Alexson The Identification of a Succinyl-CoA Thioesterase Suggests a Novel Pathway for Succinate Production in Peroxisomes J. Biol. Chem., November 18, 2005; 280(46): 38125 - 38132. [Abstract] [Full Text] [PDF]