Chain-shortening of a xenobiotic acyl compound by the peroxisomal beta-oxidation system in rat liver

When 14C-labeled N-(alpha-methylbenzyl)azelaamic acid (C9), which is an intermediate in the metabolism of N-(alpha-methylbenzyl)linoleamide, a potent hypocholesterolemic agent, was administered to rats, 84% of the radioactivity was recovered in the urine in 24 hr, which contained 66.1% of N-(alpha-methylbenzyl)glutaramic acid (C5) and 8.6% of N-(alpha-methylbenzyl)pimelamic acid (C7) as major metabolites. While 14C-labeled C9 was incubated with isolated hepatocytes, similar metabolites were found, whereas none of the metabolites with an even number of carbon atoms in the acyl side chain was detected. The activity of the chain-shortening of C9 by hepatocytes isolated from clofibrate-treated rats was stimulated to about twice that of untreated hepatocytes, in parallel with the elevation of C9-dependent H2O2-generation. A subcellular fractionation study of the liver revealed that the subcellular distribution of cyanide-insensitive C9-oxidation activity was coincident with that of catalase and of cyanide-insensitive palmitoyl-CoA oxidation. In this reaction, C7 and C5 were produced. For this reaction, the formation of C9-CoA thioester was essential as an intermediary step. These results indicate that peroxisomes are capable of shortening the acyl side-chains of drugs by beta-oxidation and, thus, suggest an additional metabolic role for peroxisomes.