1,2-dichloropropane generates phosphorylated histone H2AX via cytochrome P450 2E1-mediated metabolism

1,2-dichloropropane (1,2-DCP), a synthetic chlorinated solvent, was recently classified as carcinogenic. Genotoxic events are known as a crucial step in the initiation of cancer. However, studies on the genotoxicity of 1,2-DCP are very limited, particularly studies investigating the mechanism behind DNA damage by 1,2-DCP. In this study, the authors examined the genotoxicity of 1,2-DCP using phosphorylated histone H2AX (?-H2AX), a sensitive DNA damage marker. 1,2-DCP showed dose- (1-10 mM: 4 h) and time-dependent (1-24 h: 5 mM) ?-H2AX generation in cultured human hepatocytes (WRL-68) and cholangiocytes (MMNK-1). Additionally, ?-H2AX generation was observed in the livers of mice inhalationally exposed to 1,2-DCP at concentrations of 100, 200, and 400 ppm. During an in vitro mechanistic investigation, it was found that ?-H2AX generation by 1,2-DCP was clearly attenuated in the presence of disulfiram and 4-methylpyrazole, a specific cytochrome P450 2E1 (CYP2E1) inhibitor. Furthermore, we showed that 1,2-DCP increased the levels of intracellular reactive oxygen species (ROS), with the increase significantly inhibited by CYP2E1 inhibitors. The authors concluded that these results suggest that ROS produced via the cytochrome P450 2E1 metabolic process of 1,2-DCP was a major causal factor for ?-H2AX generation by treatment with 1,2-DCP.

Authors: Toyooka T, Yanagiba Y, Suda M, Ibuki Y, Wang RS. ;Full Source: Toxicology Letters. 2017 Mar 11. pii: S0378-4274(17)30102-9. doi: 10.1016/j.toxlet.2017.03.009. [fusion_builder_container hundred_percent=”yes” overflow=”visible”][fusion_builder_row][fusion_builder_column type=”1_1″ background_position=”left top” background_color=”” border_size=”” border_color=”” border_style=”solid” spacing=”yes” background_image=”” background_repeat=”no-repeat” padding=”” margin_top=”0px” margin_bottom=”0px” class=”” id=”” animation_type=”” animation_speed=”0.3″ animation_direction=”left” hide_on_mobile=”no” center_content=”no” min_height=”none”][Epub ahead of print] ;[/fusion_builder_column][/fusion_builder_row][/fusion_builder_container]