Cytochrome P450 2EI is responsible for the initiation of 1,2-dichloropropane-induced liver damage

1,2-Dichloropropane (1,2-DCP), a solvent, which is the main component of the cleaner used in the offset printing companies in Japan, is suspected to be the causative agent of bile duct cancer, which has been recently reported at high incidence in those offset printing workplaces. While there are some reports about the acute toxicity of I,2-DCP, no information about its metabolism related to toxicity in animals is available. As part of our efforts toward clarifying the role of I,2-DCP in the development of cancer, we studied the metabolic pathways and the hepatotoxic effect of I,2-DCP in mice with or without cytochrome P450 2EI (CYP2EI) activity. In an in vitro reaction system containing liver homogenate, I,2-DCP was only metabolized by liver tissue of wild-type mice but not by that of cyp2e I-null mice. Furthermore, the kinetics of the solvent in mice revealed a great difference between the two genotypes; I,2-DCP administration resulted in dose-dependent hepatic damage, as shown biochemically and pathologically, but this effect was only observed in wild-type mice. The nuclear factor kappa B p52 pathway was involved in the liver response to I,2-DCP. Our results clearly indicate that the oxidative metabolism of I,2-DCP in mice is exclusively catalyzed by CYP2EI, and this step is indispensable for the manifestation of the hepatotoxic effect of the solvent.