The role of cytochrome P4501A1 in 2,3,7,8-tetrachlorodibenzo-p-dioxin-induced hypertension

Several epidemiology studies have implicated AhR agonists in the development of cardiovascular disease. Polycyclic aromatic hydrocarbons (PAHs) and halogenated aromatic hydrocarbons (HAHs), both constituents of tobacco smoke, have been identified in a strong association between tobacco smokers and cardiovascular disease. More specifically, 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), the most potent agonist of the AhR, is associated with the development of cardiovascular disease in Vietnam veterans. Taken together, these observations are of concern for public health since essentially all humans are chronically exposed to two classes of AhR agonists, PAHs and HAHs, throughout their lifetimes. It is conceivable that this chronic exposure may hasten the development or severity of cardiovascular disease particularly in susceptible individuals. The long-term goal of this research is to elucidate the mechanism by which AhR activation promotes the development of cardiovascular disease using an animal model in vi which adult animals are exposed subchronically to TCDD with the body burden gradually accumulating over time. Our model revealed that subchronic TCDD exposure results in elevated blood pressure, cardiac hypertrophy, increased superoxide production in cardiovascular tissues, and decreased ACh-mediated vasorelaxation. These results demonstrated that reactive oxygen species (ROS) are contributing to the observed cardiovascular pathology. Using a vascular endothelial cell model of TCDD exposure, we observed an induction of cytochrome P4501A1 (CYP1A1) mRNA expression and activity and an increase in ROS production, which is mediated by induced CYP1A1. Therefore, we examined a CYP1A1 null mouse model to determine the role of CYP1A1 in TCDD-induced cardiovascular pathology. The cardiovascular toxicity observed following subchronic TCDD exposure of wild type mice is absent when CYP1A1 null mice are exposed to TCDD, suggesting the induction of CYP1A1 mediates these cardiovascular effects. These results demonstrate that sustained activation of AhR results in cardiovascular pathology that is downstream of CYP1A1 induction.