Omega-oxidation of Very Long-chain Fatty Acids in Human Liver Microsomes. Implications for X-linked Adrenoleukodystrophy.
From: Laboratory of Genetic Metabolic Diseases, University of Amsterdam, Academic Medical Center, 1105 AZ, Amsterdam, The Netherlands.
The Journal of biological chemistry
- Publish Date: May 2006
- ISSN: 0021-9258
- Volume: 281
- Issue: 19
- Pages: 13180-7
- Medium: Print
- Language: English
- Citation (JAMA): Sanders Robert-Jan, Ofman Rob, Duran Marinus, et al. Omega-oxidation of Very Long-chain Fatty Acids in Human Liver Microsomes. Implications for X-linked Adrenoleukodystrophy.. J. Biol. Chem. May 2006;281:13180-7
Abstract
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 study show that VLCFAs are substrates for the omega-oxidation system in human liver microsomes. Moreover, VLCFAs were not only converted into omega-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 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.
Mesh Headings (Keywords): Adrenoleukodystrophy, Cells, Cultured, Cytochrome P-450 Enzyme System, Fatty Acids, Humans, Hydroxylation, Kinetics, Microsomes, Liver, Mixed Function Oxygenases, Oxidation-Reduction
Check for Full Text / PubMed Unique Identifier (PMID): 16547005
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