Evaluation of in vivo liver genotoxic potential of Wy-14,643 and piperonyl butoxide in rats subjected to two-week repeated oral administration.

Wy-14,643 (WY), a peroxisome proliferator-activated receptor-alpha agonist, and piperonyl butoxide (PBO), a pesticide synergist, induce oxidative stress and promote hepatocarcinogenesis in the liver of rodents. These chemicals belong to a class of non-genotoxic carcinogens, but DNA damage secondary to the oxidative stress resulting from reactive oxygen species generation is suspected in rodents given these chemicals. To examine whether WY or PBO have DNA-damaging potential in livers of rats subjected to repeated oral administration for 14 days, the in vivo liver comet assay was performed in partially hepatectomized rats, and the expression of some DNA-repair genes was examined. Then, to examine whether they have genotoxic potential, the in vivo liver initiation assay was performed in rats. In the comet assay, positive results were obtained at 3 h after the last treatment of WY, and some DNA-repair genes such as Apex1, Mlh1, Xrcc5, and Gadd45 were up-regulated in the liver. In the liver initiation assay, negative results were obtained for both WY and PBO. The results of the present study suggest that WY, but not PBO, causes some DNA damage in livers of rats, but such DNA damage was repaired by the increased activity of some DNA repair genes and may not lead to a DNA mutation.