Microsomal cytochrome P-452 induction and peroxisome proliferation by hypolipidaemic agents in rat liver. A mechanistic inter-relationship.

Eight structurally diverse hypolipidaemic agents have been examined for their ability to induce the microsomal cytochrome P-452-dependent fatty acid hydroxylase system and the enzymes of peroxisomal beta-oxidation in rat liver. Using a specific ELISA method, we have shown that the cytochrome P-452 isoenzyme is induced up to ten fold by hypolipidaemic challenge, concomitant with a pronounced elevation of the peroxisomal beta-oxidation enzymes, mirrored by an increase in peroxisomal volume as determined morphometrically. In addition, the induction of cytochrome P-452 is accompanied by a decrease in the activities of cytochromes P-450b and P-450c as measured by benzphetamine N-demethylase and ethoxyresorufin O-deethylase activities respectively, the latter being more extensively reduced by hypolipidaemic treatment. A hypothesis is presented whereby an early biological response is the hypolipidaemic induction of microsomal cytochrome P-452 resulting in omega-hydroxy fatty acids and their subsequent further oxidation to dicarboxylic acids, the latter providing the proximal stimulus for peroxisomal proliferation.