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

Authors: Uno, Shigeyuki; Sakurai, Kenichi; Nebert, Daniel W; Makishima, Makoto

Published In Toxicology, (2014 Feb 28)

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.

PubMed ID: 24394547

MeSH Terms: Administration, Oral; Animals; Antioxidants/metabolism; Aorta/drug effects*; Aorta/pathology; Apolipoproteins E/genetics; Atherosclerosis/etiology*; Atherosclerosis/genetics; Atherosclerosis/pathology; Benzo(a)pyrene/administration & dosage; Benzo(a)pyrene/toxicity*; Cytochrome P-450 CYP1A1/metabolism*; DNA Adducts; Environmental Pollutants/administration & dosage; Environmental Pollutants/toxicity*; Inflammation Mediators/metabolism; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; RNA, Messenger/metabolism; Reactive Oxygen Species/metabolism; Vascular Endothelial Growth Factor A/genetics