Failure of the peroxisome proliferator WY-14,643 to induce unscheduled DNA synthesis in rat hepatocytes following in vivo treatment

Peroxisome proliferator hepatocarcinogens lack genotoxic activityin numerous in vitro assays using non-target cells which donot respond with peroxisome proliferation. Therefore, the effectof in vivo treatment with WY-14,643 on DNA repair was quantitatedin rat hepatocytes, the target cell for carcinogenesis. PalmitoylCoA oxidase and carnitine acetyltransferase activities in isolatedhepatocytes were elevated by WY-14,643 (50 mg/kg/day by gavagefor up to 5 consecutive days) and by WY-14,643 (0.1%) or di(2-ethylhexyl)phthalate (DEHP) (1.2%) feeding (for up to 28 days), indicatingperoxisome proliferation had occurred. DNA repair as unscheduledDNA synthesis (UDS) was measured autoradiographically as netnuclear grains following thymidine incorporation in primaryhepatocyte cultures. Treatment of rats with WY-14,643 (gavageor feeding) or DEHP (feeding) did not induce UDS. Addition of2-acetylaminofluorene to replicate cultures demonstrated thatWY-14,643 or DEHP treatment did not prevent repair response.Additional cultures were treated with H₂O₂ (0.8 mM H₂O₂ 3 xat 1-h intervals) to evaluate the ability of UDS to detect anyrepair which may be induced by peroxisomal metabolism. H₂O₂did not induce UDS at this concentration, nor did it prevent2-acetylaminofluorene- induced repair. UDS was, however, observedin a separate experiment using a higher concentration of H₂O₂.In summary, a highly carcinogenic peroxisome proliferator didnot induce UDS in the target cell for carcinogenesis in spiteof peroxisome proliferation following in vivo treatment.