Elsevier

Biochemical Pharmacology

Volume 39, Issue 12, 15 June 1990, Pages 1975-1981
Biochemical Pharmacology

Contribution of peroxisomal β-oxidation system to the chain-shortening of N-(α-methylbenzyl)azelaamic acid in rat liver

https://doi.org/10.1016/0006-2952(90)90618-UGet rights and content

Abstract

Hepaptic peroxisomal and mitochondrial β-oxidation of N-(α-methylbenzyl)azelaamic acid (C9), which is a possible metabolic intermediate of Melinamide, a potent hypocholesterolemic drug, were investigated. Isolated hepatocytes generated H2O2 when incubated with C9, indicating that C9 served as the substrate for peroxisomal β-oxidation. Also with isolated peroxisomes a significant activity of peroxisomal β-oxidation for C9-CoA measured by following cyanide-insensitive NAD reduction was observed, when the chain-shortened products such as C7 and C5 were detected from the incubation mixture of C9-CoA, and so NADH, acetyl-CoA and C2 units split off from C9-CoA were produced in stoichiometric amounts. In contrast, the mitochondrial β-oxidation for C9 measured by following ketone body production and antimycin A-sensitive O2 consumption was not detectable, indicating that C9 is not metabolized by mitochondrial β-oxidation. Comparative study of β-oxidation capacities in peroxisomes and mitochondria indicate that the β-oxidation of C9 occurs exclusively in peroxisomes. Also, the formation activity of C2 units liberated from C9 in intact hepatocytes reflects the peroxisomal β-oxidation activity of liver homogenates with a highly close correlation. Therefore, it is concluded that C9 can be an excellent substrate for estimating peroxisomal β-oxidation activity in intact cells.

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