Species differences in ciprofibrate induction of hepatic cytochrome P450 4A1 and peroxisome proliferation.
Six species (CD-1 mouse, Fischer 344 rat, Syrian golden hamster, Duncan-Hartley guinea pig, half-lop rabbit and marmoset monkey) were treated orally with ciprofibrate, a potent oxyisobutyrate hypolipidaemic drug for 14 days. A dose-dependent liver enlargment was observed in the mouse and rat and at the high dose level in the hamster. A marked dose-dependent increase in the 12-hydroxylation of lauric acid was observed in the treated mouse, hamster, rat, and rabbit, associated with a concomitant elevation in the specific content of cytochrome P-450 4A1 apoprotein, determined by an ELISA technique. Similarly, in these responsive species, an increase in mRNA levels coding for cytochrome P450 4A1 was observed. Lauric acid 12-hydroxylation was unchanged in the guinea pig and marmoset after ciprofibrate pretreatment, and cytochrome P-450 4A1 was not detected immunochemically in liver microsomes from these latter species. In the untreated mouse, hamster, rat, and rabbit, the 12-hydroxylation of lauric acid was more extensive than the 11-hydroxylation, whereas in the guinea pig and marmoset the activity ratios were reversed, with 11-hydroxylation predominating. Peroxisomal fatty acid beta-oxidation was markedly induced in the mouse, hamster, rat, and rabbit on treatment at the higher dose level (39-, 3-, 13- and 5-fold, respectively) and was slightly increased in the marmoset (2-fold), yet was unchanged in the guinea pig following treatment.(ABSTRACT TRUNCATED AT 250 WORDS)
D000818:Animals; D001835:Body Weight / Q000187:drug effects; D002144:Callithrix; D002995:Clofibric Acid / Q000031:analogs & derivatives* / Q000494:pharmacology; D006224:Cricetinae; D003577:Cytochrome P-450 Enzyme System / Q000096:biosynthesis* / Q000235:genetics; D004790:Enzyme Induction; D058607:Fibric Acids; D006168:Guinea Pigs; D007527:Isoenzymes / Q000096:biosynthesis* / Q000235:genetics; D008099:Liver / Q000201:enzymology*; D008297:Male; D008647:Mesocricetus; D051379:Mice; D008830:Microbodies / Q000187:drug effects*; D009929:Organ Size / Q000187:drug effects; D012313:RNA / Q000378:metabolism; D011817:Rabbits; D051381:Rats; D011916:Rats, Inbred F344; D013045:Species Specificity
D058607:Fibric Acids; D007527:Isoenzymes; D002995:Clofibric Acid; D012313:RNA; D003577:Cytochrome P-450 Enzyme System; C019304:ciprofibrate