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 carbon 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 metabolism of 22-methyl[23,23,23-2H3]tricosanoic (iso-lignoceric) acid was studied in rats in vivo and in human skin fibroblasts in culture. The deuterated iso-VLCFA was degraded to the corresponding 16- and 18-carbon iso-fatty 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. Neither 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, whereas negligible amounts were detected in the brain, suggesting that little of the fatty acid crossed the blood-brain barrier. Our data indicate that VLCFA labeled with deuterium at the omega-position of the carbon chain are suitable derivatives for the in vivo investigation of patients with defects in peroxisomal beta-oxidation because they are metabolized by the same pathways as the corresponding n-VLCFA. Moreover, as iso-VLCFA and their beta-oxidation products are readily separated from the corresponding n-fatty acids by normal chromatographic procedures, the turnover of VLCFA can be more precisely measured.
Poulos
A
A
Department of Chemical Pathology, Women's and Children's Hospital, North Adelaide, South Australia, Australia.
Stockham
P C
PC
Johnson
D W
DW
Paton
B C
BC
Beckman
K
K
Singh
H
H
D000818:Animals; D001812:Blood-Brain Barrier; D001921:Brain / Q000378:metabolism; D002478:Cells, Cultured; D002849:Chromatography, Gas; D003903:Deuterium; D005227:Fatty Acids / Q000378:metabolism*; D005347:Fibroblasts / Q000378:metabolism*; D006801:Humans; D008099:Liver / Q000378:metabolism; D010084:Oxidation-Reduction; D020675:Peroxisomes / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D015211:Zellweger Syndrome / Q000378:metabolism
D005227:Fatty Acids; D003903:Deuterium; C010210:lignoceric acid