Omega-oxidation of very long-chain fatty acids in human liver microsomes: Implications for X-linked adrenoleukodystrophy?
| Autor: | Sanders, R. -J, Ofman, R., Duran, M., Stephan Kemp, Wanders, R. J. A. |
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| Přispěvatelé: | Laboratory Genetic Metabolic Diseases, Amsterdam Gastroenterology Endocrinology Metabolism, Amsterdam Neuroscience, Amsterdam Neuroscience - Cellular & Molecular Mechanisms, Paediatric Metabolic Diseases |
| Jazyk: | angličtina |
| Rok vydání: | 2006 |
| Zdroj: | Nederlands Tijdschrift voor Klinische Chemie en Laboratoriumgeneeskunde, 31(3), 232-233. Nederlandse Vereniging voor Klinische Chemie Journal of biological chemistry, 281(19), 13180-13187. American Society for Biochemistry and Molecular Biology Inc. Scopus-Elsevier |
| ISSN: | 1570-8306 0021-9258 |
| Popis: | 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 |
| Databáze: | OpenAIRE |
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