In humans the oxidation of
phytanic acid is a peroxisomal function. To understand the possible mechanisms for the pathognomic accumulation of
phytanic acid in plasma and body fluids of
Refsum disease (RD) and
rhizomelic chondrodysplasia punctata (RCDP), we investigated activities of various steps (activation, transport, and oxidation) in the metabolism of
phytanic acid in peroxisomes isolated from cultured skin fibroblasts from control, RD, and RCDP subjects. Activation of
phytanic acid was normal in peroxisomes from both RD and RCDP. Transport of
phytanic acid or
phytanoyl-CoA in the absence or presence of
fatty acid activating cofactors (
ATP, MgCl2, and
CoASH) into peroxisomes isolated from RD and RCDP skin fibroblasts was also similar to that of peroxisomes from control fibroblasts. Defective oxidation of [(2,3)-3H]- or [1-14C]
phytanic acid, or [1-14C]
phytanoyl-CoA (substrate for the first step of alpha-oxidation) but normal oxidation of [1-14C]
alpha-hydroxyphytanic acid (substrate for the second step of the alpha-oxidation pathway) in peroxisomes from RD clearly demonstrates that excessive accumulation of
phytanic acid in plasma and body fluids of RD is due to the deficiency of
phytanic acid alpha-hydroxylase in peroxisomes. However, in RCDP peroxisomes, in addition to deficient oxidation of [1-14C]
phytanic acid or
phytanoyl-CoA or [(2,3)-3H]
phytanic acid, the oxidation of [1-14C]
alpha-hydroxyphytanic acid was also deficient, indicating that in RCDP the activities both of alpha-hydroxylation of
phytanic acid and decarboxylation of
alpha-hydroxyphytanic acid are deficient. These observations indicate that peroxisomal membrane functions (
phytanic acid activation and transport) in
phytanic acid metabolism are normal in both RD and RCDP. The defect in RD is in the alpha-hydroxylation of
phytanic acid; whereas in RCDP both alpha-hydroxylation of
phytanic acid as well as decarboxylation of
alpha-hydroxyphytanic acid are deficient.