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.
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.
J C
JC
Komen
M
M
Duran
R J A
RJ
Wanders
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