Omega-oxidation of very long-chain fatty acids in human liver microsomes. Implications for X-linked adrenoleukodystrophy.
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.
Laboratory of Genetic Metabolic Diseases, University of Amsterdam, Academic Medical Center, 1105 AZ, Amsterdam, The Netherlands.
Robert-Jan
RJ
Sanders
Laboratory of Genetic Metabolic Diseases, University of Amsterdam, Academic Medical Center, 1105 AZ, Amsterdam, The Netherlands.
Rob
R
Ofman
Laboratory of Genetic Metabolic Diseases, University of Amsterdam, Academic Medical Center, 1105 AZ, Amsterdam, The Netherlands.
Marinus
M
Duran
Laboratory of Genetic Metabolic Diseases, University of Amsterdam, Academic Medical Center, 1105 AZ, Amsterdam, The Netherlands.
Stephan
S
Kemp
Laboratory of Genetic Metabolic Diseases, University of Amsterdam, Academic Medical Center, 1105 AZ, Amsterdam, The Netherlands. Electronic address: r.j.wanders@amc.uva.nl.
Ronald J A
RJA
Wanders
D000326:Adrenoleukodystrophy / Q000378:metabolism*; D002478:Cells, Cultured; D065607:Cytochrome P-450 Enzyme Inhibitors; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism; D005227:Fatty Acids / Q000737:chemistry* / Q000378:metabolism*; D006801:Humans; D006900:Hydroxylation; D007700:Kinetics; D008862:Microsomes, Liver / Q000378:metabolism*; D006899:Mixed Function Oxygenases / Q000037:antagonists & inhibitors / Q000378:metabolism; D010084:Oxidation-Reduction
D065607:Cytochrome P-450 Enzyme Inhibitors; D005227:Fatty Acids; D003577:Cytochrome P-450 Enzyme System; D006899:Mixed Function Oxygenases