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.
Sharma
R
R
University of Surrey, Department of Biochemistry, Guildford, U.K.
Lake
B G
BG
Foster
J
J
Gibson
G G
GG
D000818:Animals; D002455:Cell Division / Q000187:drug effects; D003580:Cytochromes / Q000096:biosynthesis*; D004790:Enzyme Induction; D004797:Enzyme-Linked Immunosorbent Assay; D005227:Fatty Acids / Q000378:metabolism; D000960:Hypolipidemic Agents / Q000494:pharmacology*; D007527:Isoenzymes / Q000032:analysis; D008099:Liver / Q000187:drug effects* / Q000201:enzymology; D008297:Male; D008830:Microbodies / Q000187:drug effects* / Q000378:metabolism; D010084:Oxidation-Reduction; D051381:Rats; D011919:Rats, Inbred Strains
D003580:Cytochromes; D005227:Fatty Acids; D000960:Hypolipidemic Agents; D007527:Isoenzymes; C046362:cytochrome P-452