Mode of action analysis for mouse liver tumor formation by MGK-264 and human relevance.

MGK-264, an insecticidal synergist, has been shown to increase the incidence of liver tumors in male and female mice. As MGK-264 is not a genotoxic compound, a series of investigative studies were conducted to elucidate the mode of action (MoA) for liver tumor production by MGK-264. Male and female CD-1 mice were given diets containing MGK-264 at 400, 3000, and 6000 ppm for 7 and/or 14 days. Treatment with MGK-264 caused activation of the constitutive androstane receptor (CAR), which resulted in liver hypertrophy, induction of cytochrome P450 CYP2B subfamily enzymes, and increased replicative DNA synthesis (RDS) in the liver in male and female mice. In contrast, these changes were not observed in the livers of male CAR and pregnane X receptor (PXR) knockout (CAR KO/PXR KO) mice treated with MGK-264. The treatment of primary human hepatocytes with 1-30 μM MGK-264 increased CYP2B and CYP3A mRNA expression, but had no effect on hepatocyte RDS. Similarly, the treatment of chimeric mice with human hepatocytes with 6000 ppm MGK-264 in the diet for 7 days resulted in increased CYP2B and CYP3A mRNA expression, but had no significant effect on human hepatocyte RDS. In summary, based on these investigative studies, MGK-264 is a CAR activator at carcinogenic dose levels in mouse liver. A robust MoA for MGK-264-induced mouse liver tumor formation has been established and is not considered plausible for humans on the basis of qualitative differences between humans and mice. This conclusion is supported by data from human epidemiology studies with CAR activators.