The effect of peroxisome proliferators on the metabolism and spectral interaction of endogenous substrates of cytochrome P-450 in rat hepatic microsomes.
The peroxisome proliferators clofibric acid and di-(2-ethylhexyl)-phthalate (DEHP) preferentially induced the 12-hydroxylation, compared to the 11-hydroxylation, of lauric acid in rat liver microsomes. A marked increase in the affinity of spectral interaction of this substrate with cytochrome P-450 was also observed. In addition, both clofibric acid and DEHP treatment produced a marked effect on the profile of site- and stereo-specific microsomal metabolites of testosterone. These results demonstrate that both peroxisome proliferators induce similar form(s) of cytochrome P-450 which are active in the metabolism of endogenous substrates of cytochrome P-450. The possible relevance of these findings to the hepatotoxicity of peroxisome proliferators is discussed.
D000818:Animals; D016718:Arachidonic Acid; D001095:Arachidonic Acids / Q000378:metabolism; D002994:Clofibrate / Q000031:analogs & derivatives*; D002995:Clofibric Acid / Q000494:pharmacology*; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism*; D004051:Diethylhexyl Phthalate / Q000494:pharmacology*; D006900:Hydroxylation; D019787:Linoleic Acid; D008041:Linoleic Acids / Q000378:metabolism; D008297:Male; D008830:Microbodies / Q000187:drug effects; D008862:Microsomes, Liver / Q000187:drug effects* / Q000378:metabolism; D010795:Phthalic Acids / Q000494:pharmacology*; D051381:Rats; D011919:Rats, Inbred Strains; D013739:Testosterone / Q000378:metabolism
D001095:Arachidonic Acids; D008041:Linoleic Acids; D010795:Phthalic Acids; D016718:Arachidonic Acid; D013739:Testosterone; D002995:Clofibric Acid; D003577:Cytochrome P-450 Enzyme System; D019787:Linoleic Acid; D004051:Diethylhexyl Phthalate; D002994:Clofibrate