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J. Biol. Chem., Vol. 281, Issue 19, 13180-13187, May 12, 2006

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-Oxidation of Very Long-chain Fatty Acids in Human Liver Microsomes

IMPLICATIONS FOR X-LINKED ADRENOLEUKODYSTROPHY^*

From the Laboratory of Genetic Metabolic Diseases, University of Amsterdam, Academic Medical Center, 1105 AZ, Amsterdam, The Netherlands

X-linked adrenoleukodystrophy (X-ALD) is a severe neurodegenerative disorder biochemically characterized by elevated levels of very long-chain fatty acids (VLCFA). Excess levels of VLCFAs are thought to play an important role in the pathogenesis of X-ALD. Therefore, therapeutic approaches for X-ALD are focused on the reduction or normalization of VLCFAs. In this study, we investigated an alternative oxidation route for VLCFAs, namely -oxidation. The results described in this study show that VLCFAs are substrates for the -oxidation system in human liver microsomes. Moreover, VLCFAs were not only converted into -hydroxy fatty acids, but they were also further oxidized to dicarboxylic acids via cytochrome P450-mediated reactions. High sensitivity toward the specific P450 inhibitor 17-octadecynoic acid suggested that -hydroxylation of VLCFAs is catalyzed by P450 enzymes belonging to the CYP4A/F subfamilies. Studies with individually expressed human recombinant P450 enzymes revealed that two P450 enzymes, i.e. CYP4F2 and CYP4F3B, participate in the -hydroxylation of VLCFAs. Both enzymes belong to the cytochrome P450 4F subfamily and have a high affinity for VLCFAs. In summary, this study demonstrates that VLCFAs are substrates for the human -oxidation system, and for this reason, stimulation of the in vivo VLCFA -oxidation pathway may provide an alternative mode of treatment to reduce the levels of VLCFAs in patients with X-ALD.

Received for publication, December 19, 2005 , and in revised form, March 16, 2006.

^* This work was supported by Prinses Beatrix Fonds Grant MAR 02-0116, the Netherlands Organization for Scientific Research Grant NWO-MW 903-42-077, and a grant from the European Leukodystrophy Association. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ To whom correspondence should be addressed: Laboratory of Genetic Metabolic Diseases (Rm. F0-224), Academic Medical Center, Meibergdreef 9, 1105 AZ, Amsterdam, The Netherlands. Tel.: 31-20-5665958; Fax: 31-20-6962596; E-mail: r.j.wanders{at}amc.uva.nl.

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