Omega-oxidation of very long-chain fatty acids in human liver microsomes: Implications for X-linked adrenoleukodystrophy

doi:10.1074/jbc.M513481200

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Papers In Press, published online ahead of print March 17, 2006
J. Biol. Chem, 10.1074/jbc.M513481200
Submitted on December 19, 2005
Revised on March 16, 2006
Accepted on March 17, 2006

Omega-oxidation of very long-chain fatty acids in human liver microsomes: Implications for X-linked adrenoleukodystrophy

Robert-Jan Sanders, Rob Ofman, Marinus Duran, Stephan Kemp, and Ronald J. A. Wanders

Clinical Chemistry and Pediatrics, Academic Medical Center, Amsterdam, P. O. Box 22700 1100 DE

Corresponding Author: r.j.wanders{at}amc.uva.nl

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 $omega$ -oxidation. The results described in this paper show that VLCFAs are substrates for the $omega$ -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 towards the specific P450 inhibitor 17-octadecynoic acid suggested that $omega$ -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 $omega$ -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 $omega$ -oxidation system and for this reason stimulation of the in vivo VLCFA $omega$ -oxidation pathway may provide an alternative mode of treatment to reduce the levels of VLCFAs in patients with X-ALD.

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