Dose-Related Effects of the Hepatocarcinogen, Wy-14,643, on Peroxisomes and Cell Replication

Dose-Related Effects of the Hepatocarcinogen, Wy-14,643, onPeroxisomes and Cell Replication. WADA, N., MARSMAN, D. S.,AND POPP, J. A. (1992). Fundam. Appl. Toxicol. 18, 149–154. The dose and time dependency of peroxisome proliferation andhepatocyte replication was evaluated in the liver of rats fedthe peroxisome proliferator and hepatocarcinogen, Wy-14,643.Male F344 rats were fed NIH07 diet blended with Wy-14,643 at0, 5, 10, 50, 100, or 1000 ppm for 1, 3, 6, or 13 weeks. Hepatomegalywas induced by Wy-14,643 at all doses and at all time points.Peroxisome proliferation was present in rats fed 5 ppm Wy-14,643as early as 1 week, as determined by the peroxisome-specificNAD⁺ reduction of palmitoyl CoA (PCO) and the peroxisome-associatedactivity of carnitine acetyltransferase (CAT) (5-and 11-foldover control, respectively). The elevations of PCO and CAT weredose-dependent from 5 to 50 ppm and then plateaued from 50 to1000 ppm throughout the treatment period. Hepatocellular replication,evaluated by nuclear histoautoradiography ([³H]thymidine labeling,6-day infusion), was increased in all Wy-14,643 dose groupsafter 1 week of treatment (5 ppm, 4-fold; 10 ppm, 5-fold; 50ppm, 13-fold; 100 ppm, 12-fold; and 1000 ppm, 13-fold over controls).However, in 5 and 10 ppm groups this cell replication returnedto control levels by 3 weeks. In contrast, 50, 100, and 1000ppm groups had sustained increases in cell replication up to13 weeks (13 weeks: 6-, 7-, and 9-fold over controls, respectively).We have demonstrated that Wy-14,643 can induce peroxisome proliferationat 5 ppm, a dose 200 times lower than the dose shown to be highlyhepatocarcinogenic in rats (100% incidence by 60 weeks). Incontrast, 50 ppm was identified as the minimal dose which inducedsustained cell replication in rat liver. These data show thatperoxisome proliferation can be dissected from sustained cellreplication for correlating either peroxisome induction or cellreplication with tumor formation. These results provide importantinformation that can be used to design carcinogenicity experimentsto test if peroxisome proliferation and/or chronic enhancementof cell replication predictive risk factors for hepatocarcinogenieity.