Early Effects of CI-924 on hepatic peroxisome proliferation, microsomal enzyme induction, PCNA, and apoptosis in B6C3F1 mice and Wistar rats

Abstract

The lipid lowering agent 5,5'[[1,1'-biphenyl]-2,5-diylbis(oxy)]bis[2,2-dimethylpentanoic acid] (CI-924) is a peroxisome proliferator in rats and mice, but increased the incidence of hepatic tumors in mice only. Male and female B6C3F1 mice and albino Wistar rats were treated with CI-924 at doses of 0, 25 and 75 mg/kg for 1, 3, 7 and 28 days. Our aim was to identify species differences potentially related to tumorigenicity and to establish the time course of early events related to or associated with peroxisome proliferation. After 24 h of exposure to CI-924 in the diet there were increases in carnitine acyl transferase and CYP4A1 activity in mice at 25 and 75 mg/kg. In rats, carnitine acyl transferase activity was increased after 24 h and CYP4A1 activity increased after 3 days at 75 mg/kg. Acyl CoA oxidase activity was increased at both doses in male and female rats and mice by 3 days. In general the changes in enzyme activity were of greater magnitude in rats. In contrast to the rapid peroxisome proliferation, increases in the amount of PCNA were observed in CI-924 treated rats and mice at later times after administration and only at 75 mg/kg. PCNA was increased to a similar extent in both rats and mice, while apoptosis was decreased at both doses of CI-924 after 3 days in female rats, 7 days in male rats, and was largely unchanged in mice. It was concluded that the sequence of peroxisome proliferation was generally similar in rats and mice. Early changes in cell proliferation and programmed cell death were not directly correlated with subsequent CI-924-induced hepatotumorigenicity.

Regulation of cell proliferation and cell death by peroxisome proliferators

“…For example, Roberts et al (1995) demonstrated that the basal frequency of apoptosis in rat liver was 0.030%, and that after 10 days of treatment of rats with the peroxisome proliferator nafenopin, the frequency of apoptosis had decreased to 0.002%. Another peroxisome proliferator, the drug CI-924, decreased the frequency of apoptosis in rat liver after 7 and 28 days (from 0.66 to 0.41% and 1.47 to 0.32%, respectively) but not mouse liver, even though other responses (peroxisomal enzyme induction and hepatocyte proliferation) were similar in both species (Hofstra et al, 1997). Surprisingly, few studies have evaluated this effect of peroxisome proliferators on apoptosis in vivo, although there are many reports of this response to peroxisome proliferators in cultured hepatocytes in vitro.…”

“…To date, there are no published studies extending these in vitro findings to the in vivo situation, i.e., investigation of modulation of apoptosis in livers of PPAR␣ knockout mice following in vivo treatment. As discussed above, only one published study evaluated the effect of a peroxisome proliferator on apoptosis in wild type mice, with no effect of treatment observed (Hofstra et al, 1997).…”