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METABOLISM, TRANSPORT, AND PHARMACOGENOMICS

CYP4 Isoform Specificity in the -Hydroxylation of Phytanic Acid, a Potential Route to Elimination of the Causative Agent of Refsum's Disease

Departments of Pharmaceutical Chemistry (F.X., P.R.O.d.M.) and Biopharmaceutical Sciences (V.Y.N., D.L.K.), University of California, San Francisco, California

The saturated C20 isoprenoid phytanic acid is physiologically derived from phytol released in the degradation of chlorophyll. The presence of a C-3 methyl group in this substrate blocks normal -oxidation, so phytanic acid degradation primarily occurs by initial peroxisomal -oxidation to shift the register of the methyl group. However, individuals with Refsum's disease are genetically deficient in the required phytanoyl-CoA -hydroxylase and suffer from neurological pathologies caused by the accumulation of phytanic acid. Recent work has shown that phytanic acid can also be catabolized by a pathway initiated by -hydroxylation of the hydrocarbon chain, followed by oxidation of the alcohol to the acid and conventional -oxidation. However, the enzymes responsible for the -hydroxylation of phytanic acid have not been identified. In this study, we have determined the activities of all of the rat and human CYP4A enzymes and two of the rat CYP4F enzymes, with respect to the -hydroxylation of phytanic acid. Furthermore, we have shown that the ability to -hydroxylate phytanic acid is elevated in microsomes from rats pretreated with clofibrate. The results support a possible role for CYP4 enzyme elevation in the elimination of phytanic acid in Refsum's disease patients.

Address correspondence to: Dr. Paul Ortiz de Montellano, University of California, Genentech Hall GH-N572D, 600 16th Street, San Francisco, CA 94143-2280. E-mail: ortiz{at}cgl.ucsf.edu

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