The 3-methyl-branched
fatty acid phytanic acid is degraded by the peroxisomal alpha-oxidation route because the 3-methyl group blocks beta-oxidation. In
adult Refsum disease (ARD), peroxisomal alpha-oxidation is defective, which is caused by mutations in the gene coding for
phytanoyl-CoA hydroxylase in the majority of ARD patients. As a consequence,
phytanic acid accumulates in tissues and body fluids. This study focuses on an alternative route of
phytanic acid degradation, omega-oxidation. The first step in omega-oxidation is hydroxylation at the omega-end of the
fatty acid, catalyzed by a member of the
cytochrome P450 multienzyme family. To study this first step, the formation of hydroxylated intermediates was studied in rat liver microsomes incubated with
phytanic acid and
NADPH. Two hydroxylated metabolites of
phytanic acid were formed, omega- and (omega-1)-hydroxyphytanic
acid (ratio of formation, 5:1). The formation of omega-hydroxyphytanic
acid was
NADPH dependent and inhibited by
imidazole derivatives. These results indicate that
phytanic acid undergoes omega-hydroxylation in rat liver microsomes and that an
isoform of
cytochrome P450 catalyzes the first step of
phytanic acid omega-oxidation.