Potential ability of human cytochrome P450 isozymes to metabolize dioxins involved in the Yusho incident

Abstract

Dioxins and dioxin-like compounds, such as polychlorinated biphenyls (PCBs), were responsible for the 1968 Yusho incident that poisoned thousands of people in western Japan and continue to linger in their blood even today. Within the human body, the cytochrome P450 (CYP) enzyme system has some ability to metabolize dioxins. In this study, we performed in silico docking simulations of the interactions between seven CYP isozymes (i.e., CYP1A1, CYP1A2, CYP1B1, CYP2A6, CYP2B6, CYP2C9, and CYP3A4) and 21 dioxins (i.e., four non-ortho coplanar PCBs, seven polychlorinated dibenzo-p-dioxins, and 10 polychlorinated dibenzofurans) to evaluate the CYP-dependent metabolic potencies of the dioxins. The results suggested that CYP2A6 may be capable of metabolizing 11 dioxins, whereas CYP2B6 may be capable of metabolizing nine dioxins. Notably, only CYP2A6 may be capable of metabolizing 2,3,4,7,8-PeCDF, which accumulates at high concentrations in Yusho patients. These results indicate that CYP2A6 plays an important role in the metabolization of dioxins.