Characterization of phytanic acid ω-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 β-oxidation, it is broken down by peroxisomal α-oxidation. Adult Refsum disease patients accumulate phytanic acid as a result of an impairment in peroxisomal α-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 ω-oxidation. During ω-oxidation a fatty acid is hydroxylated at its ω-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 ω-hydroxylation would lead to the formation of phytanedioic acid, which can be degraded by β-oxidation from the ω-end. Here, we show that phytanic acid indeed undergoes ω- and (ω-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 ω-hydroxylation may increase the flux through the ω-oxidation pathway, causing increased clearance of phytanic acid in ARD patients. Hence, this alternative catabolic pathway is of potential therapeutic relevance.