Dose-response relationships of hepatic acyl-CoA oxidase and catalase activity and liver mitogenesis induced by the peroxisome proliferator ciprofibrate in C57BL/6N and BALB/c mice.

The dose-response for key hepatic effects of the peroxisome proliferator ciprofibrate, 2-[4-(2,2-dichlorocyclopropyl)phenoxy]-2- methylpropanoic acid, was delineated in mice and strain differences in response were demonstrated. Ciprofibrate was fed at concentrations ranging from 0.1 to 250 ppm to male C57BL/6N and BALB/c mice and the induction of hepatic acyl-CoA oxidase and catalase, peroxisomal enzymes involved in the formation and degradation of hydrogen peroxide, and liver hepatomegaly and mitogenesis were measured. No effect was found for enzyme induction at 5.0 ppm or less in either strain. Likewise, hepatomegaly was not found at 5.0 ppm, but mitogenesis was observed in BALB/c mice at 1.0 ppm. C57BL/6N mice demonstrated greater basal and postexposure acyl-CoA oxidase activity than BALB/c mice, while BALB/c mice demonstrated greater catalase activity and induction of liver mitogenesis. The threshold exposure level for induction of acyl-CoA oxidase activity was approximately the same as that for induction of mitogenesis in C57BL/6N mice; in contrast, the threshold exposure level for induction of acyl-CoA oxidase activity was at least one order of magnitude greater than that required for induction of mitogenesis in BALB/c mice. Thus, the induction of the peroxisomal enzyme involved in the formation of hydrogen peroxide and increased mitogenesis are not mechanistically linked. The differential effects observed in the two mouse strains provide the basis for development of a quantitative model of peroxisome proliferator-induced carcinogenicity in which cellular effects can be related to carcinogenicity.