Species differences in ciprofibrate induction of hepatic cytochrome p450 4A1 and peroxisome proliferation

✍ Scribed by Makowska, Janet M. ;Gibson, G. Gordon ;Banner, Frank W.

• Publisher: John Wiley and Sons
• Year: 1992
• Tongue: English
• Weight: 849 KB
• Volume: 7
• Category: Article
• ISSN: 0887-2082
• DOI: 10.1002/jbt.2570070308

✦ Synopsis

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 dosedependent liver enlargement 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 ll-hydroxylation, whereas in the guinea pig and marmoset the activity ratios were reversed, with ll-hydroxylation predominating. Peroxisomal fatty acid p-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 (Zfold), yet was unchanged in the guinea pig following treatment. In the marmoset the increase in peroxisomal &oxidation was 3-to 4-fold at the high dose level; however, the dose levels used in the marmoset were 20 and 100 mg/kg as opposed to 2 and 20 mg/kg