title: 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.
authors.affiliation: Division of Biochemistry, Department of Biomedical Sciences, Nihon University School of Medicine, Itabashi-ku, Tokyo 173-8610, Japan.
authors.forename: Shigeyuki
authors.initials: S
authors.lastname: Uno
authors.affiliation: Division of Breast and Endocrine Surgery, Department of Surgery, Nihon University School of Medicine, Itabashi-ku, Tokyo 173-8610, Japan.
authors.forename: Kenichi
authors.initials: K
authors.lastname: Sakurai
authors.affiliation: Department of Environmental Health and Center for Environmental Genetics, University of Cincinnati Medical Center, P.O. Box 670056, Cincinnati, OH 45267-0056, USA.
authors.forename: Daniel W
authors.initials: DW
authors.lastname: Nebert
authors.affiliation: Division of Biochemistry, Department of Biomedical Sciences, Nihon University School of Medicine, Itabashi-ku, Tokyo 173-8610, Japan. Electronic address: makishima.makoto@nihon-u.ac.jp.
authors.forename: Makoto
authors.initials: M
authors.lastname: Makishima
mesh_terms: D000284:Administration, Oral; D000818:Animals; D000975:Antioxidants / Q000378:metabolism; D001011:Aorta / Q000187:drug effects* / Q000473:pathology; D001057:Apolipoproteins E / Q000235:genetics; D050197:Atherosclerosis / Q000209:etiology* / Q000235:genetics / Q000473:pathology; D001564:Benzo(a)pyrene / Q000008:administration & dosage / Q000633:toxicity*; D019363:Cytochrome P-450 CYP1A1 / Q000378:metabolism*; D018736:DNA Adducts; D004785:Environmental Pollutants / Q000008:administration & dosage / Q000633:toxicity*; D018836:Inflammation Mediators / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D012333:RNA, Messenger / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism; D042461:Vascular Endothelial Growth Factor A / Q000235:genetics
chemical_list: D000975:Antioxidants; D001057:Apolipoproteins E; D018736:DNA Adducts; D004785:Environmental Pollutants; D018836:Inflammation Mediators; D012333:RNA, Messenger; D017382:Reactive Oxygen Species; D042461:Vascular Endothelial Growth Factor A; D001564:Benzo(a)pyrene; D019363:Cytochrome P-450 CYP1A1
keywords: Apoe(−/−) mice; Atherosclerosis; Benzo[a]pyrene; Cyp1a1(−/−) mice; DNA adduct formation; Reactive oxygen species