COMPARATIVE INDUCTION OF CYTOCHROME-P450IVA1 AND PEROXISOME PROLIFERATION BY CIPROFIBRATE IN THE RAT AND MARMOSET

Chronic ciprofibrate administration resulted in distinct differences in hepatic responses between the two species examined. In the rat, hepatomegaly was observed with the coordinate induction of carnitine acetyl-transferase, peroxisomal beta-oxidation and cytochrome P4501VA1 activities. The latter induction of cytochrome P4501VA1-dependent fatty acid hydroxylase activity was specific to this cytochrome P450 sub family, as ciprofibrate pretreatment resulted in an inhibition of the enzyme activities associated with the cytochrome P450 IIB and IA sub-families. Induction of mitochondrial enzymes were also noted in the rat, but at a substantially lower level than the microsomal and peroxisomal enzyme changes noted above. The majority of these enzyme changes were reversible in the rat after a 4-week, inducer-free period. In contrast, the marmoset displayed a different pattern of enzyme changes in response to ciprofibrate and at the high dose level, inhibition of microsomal fatty acid hydroxylase activity was observed in addition to no change in carnitine acetyltransferase activity. Although peroxisomal beta-oxidation activity was induced in the marmoset, the specific activity was 10-fold lower than in the rat, concomitant with only minimum changes in the liver: body weight ratio. Taken collectively, our data have demonstrated that the marmoset is relatively refractory to ciprofibrate-induced liver enzyme changes with the implication that the extrapolation of the associated hepatotoxicity clearly documented in rodents must be viewed with extreme caution in non-human primates.