Metabolism of trideuterated iso-lignoceric acid in rats in vivo and in human fibroblasts in culture

Saturated very long chain fatty acids (fatty acids with greater than 22 car bon atoms; VLCFA) accumulate in peroxisomal disorders, but there is little information on their turnover in patients. To determine the suitability of using stable isotope-labeled VLCFA in patients with these disorders, the me tabolism of 22-methyl [23,23,23-H-2(3)]tricosanoic (iso-lignoceric) acid wa s studied in rats in vivo and in human skin fibroblasts in culture. The deu terated iso-VLCFA was degraded to the corresponding 16- and 18-carbon iso-f atty acids by rats in vivo and by normal human skin fibroblasts in culture, but there was little or no degradation in peroxisome-deficient (Zellweger' s syndrome) fibroblasts, indicating that its oxidation was peroxisomal. Nei ther the 14-, 20-, and 22-carbon iso-fatty acids nor the corresponding odd- chain metabolites could be detected. In the rat, the organ containing most of the iso-lignoceric acid, and its breakdown products, was the liver, wher eas negligible amounts were detected in the brain, suggesting that little o f the fatty acid crossed the blood-brain barrier. Our data indicate that VL CFA labeled with deuterium at the omega-position of the carbon chain are su itable derivatives for the in vivo investigation of patients with defects i n peroxisomal beta-oxidation because they are metabolized by the same pathw ays as the corresponding n-VLCFA. Moreover,as iso-VLCFA and their beta-oxid ation products are readily separated from the corresponding n-fatty acids b y normal chromatographic procedures, the turnover of VLCFA can be more prec isely measured.