EARLY EFFECTS OF CI-924 ON HEPATIC PEROXISOME PROLIFERATION, MICROSOMAL-ENZYME INDUCTION, PCNA, AND APOPTOSIS IN B6C3F1 MICE AND WISTAR RATS

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 rat s 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 ai m was to identify species differences potentially related to tumorigen icity and to establish the time course of early events related to or a ssociated 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 t ransferase activity was increased after 24 h and CYP4A1 activity incre ased 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 c ontrast 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 sim ilar extent in both rats and mice, while apoptosis was decreased at bo th doses of CI-924 after 3 days in female rats, 7 days in male rats, a nd was largely unchanged in mice. It was concluded that the sequence o f peroxisome proliferation was generally similar in rats and mice. Ear ly changes in cell proliferation and programmed cell death were not di rectly correlated with subsequent CI-924-induced hepatotumorigenicity.