Ketoconazole and other imidazole derivatives are potent inhibitors of peroxisomal phytanic acid alpha-oxidation.
The imidazole antimycotics like ketoconazole, clotrimazole, bifonazole, miconazole and CO, known as powerful inhibitors of cytochrome P-450, are potent inhibitors of peroxisomal phytanic acid alpha-oxidation to pristanic acid suggesting the possible involvement of the cytochrome P-450 mono-oxygenase system in this oxidation. In contrast to the inhibition of the oxidation of [1-14C]phytanic acid, [1-14C]phytanoyl-CoA and [(2,3)-3H]phytanic acid, these drugs and CO have no effect on the oxidation of [1-14C]alpha-hydroxy phytanic acid indicating that these drugs and CO inhibit only the alpha-hydroxylation of phytanic acid. These studies using purified peroxisomes from liver and cultured human skin fibroblasts and Hep G2 cells clearly demonstrate that alpha-hydroxylation, an intermediate step in the alpha-oxidation of phytanic acid found to be impaired in Refsum Disease, is mediated by cytochrome P-450 containing enzyme.
Department of Pediatrics, Medical University of South Carolina, Charleston 29525, USA.
K
K
Pahan
M
M
Khan
B T
BT
Smith
I
I
Singh
D002248:Carbon Monoxide / Q000494:pharmacology; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology*; D007654:Ketoconazole / Q000494:pharmacology*; D008830:Microbodies / Q000187:drug effects; D010084:Oxidation-Reduction; D010831:Phytanic Acid / Q000037:antagonists & inhibitors*
D007093:Imidazoles; D010831:Phytanic Acid; D002248:Carbon Monoxide; D007654:Ketoconazole