Characterization of phytanic acid omega-hydroxylation in human liver microsomes.
Phytanic acid is a 3-methyl branched-chain fatty acid which originates from dietary sources. Since the 3-methyl group blocks regular beta-oxidation, it is broken down by peroxisomal alpha-oxidation. Adult Refsum disease patients accumulate phytanic acid as a result of an impairment in peroxisomal alpha-oxidation, caused by the deficient activity of the enzyme phytanoyl-CoA hydroxylase in the majority of patients. In this paper, we studied an alternative degradation route for phytanic acid, namely omega-oxidation. During omega-oxidation a fatty acid is hydroxylated at its omega-end by a member of the cytochrome P450 multi-enzyme family. Subsequently, an alcohol dehydrogenase converts the formed hydroxyl group into an aldehyde, which is then converted into a carboxyl-group by an aldehyde dehydrogenase. In case of phytanic acid omega-hydroxylation would lead to the formation of phytanedioic acid, which can be degraded by beta-oxidation from the omega-end. Here, we show that phytanic acid indeed undergoes omega- and (omega-1)-hydroxylation in pooled human liver microsomes in an NADPH-dependent manner with a ratio of 15:1. Studies with imidazole antimycotics indicate that these reactions are catalyzed by one or more cytochrome P450 enzymes. Induction of the cytochrome P450 involved in phytanic acid omega-hydroxylation may increase the flux through the omega-oxidation pathway, causing increased clearance of phytanic acid in ARD patients. Hence, this alternative catabolic pathway is of potential therapeutic relevance.
Komen
J C
JC
Laboratory Genetic Metabolic Diseases, Departments of Clinical Chemistry and Pediatrics, Emma Childrens Hospital, University of Amsterdam, Academic Medical Center, P.O. Box 22700, 1100 DE Amsterdam, The Netherlands.
Duran
M
M
Wanders
R J A
RJ
D000328:Adult; D000445:Aldehyde Oxidoreductases / Q000378:metabolism; D000818:Animals; D002384:Catalysis; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism*; D006801:Humans; D006900:Hydroxylation; D008862:Microsomes, Liver / Q000378:metabolism*; D009249:NADP / Q000378:metabolism; D010084:Oxidation-Reduction; D010831:Phytanic Acid / Q000378:metabolism*; D051381:Rats; D012035:Refsum Disease / Q000378:metabolism
D010831:Phytanic Acid; D009249:NADP; D003577:Cytochrome P-450 Enzyme System; D000445:Aldehyde Oxidoreductases