Protective role of cytochrome P450 1A1 (CYP1A1) against benzo[a]pyrene-induced toxicity in mouse aorta

Abstract

Benzo[a]pyrene (BaP) is an environmental pollutant produced by combustive processes, such as cigarette smoke and coke ovens, and is implicated in the pathogenesis of atherosclerosis. Cytochrome P450 1A1 (CYP1A1) plays a role in both metabolic activation and detoxication of BaP in a context-dependent manner. The role of CYP1A1 in BaP-induced toxicity in aorta remains unknown. First, we fed Apoe(−/−) mice an atherogenic diet plus BaP and found that oral BaP-enhanced atherosclerosis is associated with increased reactive oxygen species (ROS) and inflammatory markers, such as plasma tumor necrosis factor levels and aortic mRNA expression of vascular endothelial growth factor A (Vegfa). We next examined the effect of an atherogenic diet plus BaP on ROS and inflammatory markers in Cyp1a1(−/−) mice. Although this treatment was not sufficient to induce atherosclerotic lesions in Cyp1a1(−/−) mice, plasma antioxidant levels were decreased in Cyp1a1(−/−) mice even in the absence of BaP treatment. The atherogenic diet plus BaP effectively elevated plasma ROS levels and expression of atherosclerosis-related genes, specifically Vegfa, in Cyp1a1(−/−) mice compared with wild-type mice. BaP treatment increased Vegfa mRNA levels in mouse embryonic fibroblasts from Cyp1a1(−/−) mice but not from wild-type mice. BaP-induced DNA adduct formation was increased in the aorta of Cyp1a1(−/−) mice, but not wild-type or Apoe(−/−) mice, and the atherogenic diet decreased BaP-induced DNA adducts in Cyp1a1(−/−) mice compared with mice on a control diet. These data suggest that ROS production contributes to BaP-exacerbated atherosclerosis and that CYP1A1 plays a protective role against oral BaP toxicity in aorta.