Abstract
The peroxisomal β-oxidation of ω-phenyl fatty acids (PFAs) as model compounds for xenobiotic acyl compounds was investigated. In isolated hepatocytes, ω-phenyllauric acid (PFA 12) was chain-shortened to PFAs having an even number of carbon atoms in the acyl side chain. Associated with this reaction, H 2O 2 generation was observed, the rate of which was markedly enhanced by clofibrate treatment of rats. Also when using isolated peroxisomes, such a chain-shortening of PFA 12 occurred, associated with stoichiometrical production of NADH and acetyl-CoA. The CoA-ester form of PFA 12 as a substrate and NAD as a cofactor were required in this reaction, indicating the participation of peroxisomal β-oxidation in the chain-shortening of PFA 12. When using PFAs with various chain lengths, the rates of H 2O 2 generation measured as the peroxisomal β-oxidation in isolated hepatocytes were similar to those with the corresponding fatty acids, whereas the rates of ketone body production measured as the mitochondrial β-oxidation were much lower than that with any fatty acid examined. From the study with isolated mitochondria and purified enzymes, it was found that the mitochondrial β-oxidation of PFAs was carnitine-dependent, and that the activities of carnitine palmitoyltransferase for PFA-CoAs are low. Moreover, the activities of acyl-CoA dehydrogenase for PFA-CoAs were lower than those for fatty acyl-CoAs, while the activities of acyl-CoA oxidase for PFA-CoAs were comparable to those for fatty acyl-CoAs. As a result, relatively long chain PFAs were hardly subjected to mitochondrial β-oxidation. Based on the maximum enzyme activities of the β-oxidation, which were measured by following acyl-CoA-dependent NAD reduction in isolated peroxisomes and O 2 consumption in isolated mitochondria, about 60% of the β-oxidation of PFA 12 in the rat liver was peroxisomal. In clofibrate-treated rats, the value reached about 85%. From these results it is concluded that the peroxisome is one of the important sites of degradation of xenobiotic acyl compounds.
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More From: Biochimica et Biophysica Acta (BBA) - Lipids and Lipid Metabolism
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