The Role of Cytochrome P450 1B1 in Dibenzo[ a,l ]pyrene-induced Carcinogenesis |
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Authors: | Andreas Luch Helmut Greim Jeroen T. M. Buters Brinda Mahadevan William M. Baird Johannes Doehmer |
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Affiliation: | 1. Institute of Toxicology and Environmental Hygiene , Technical University of Munich , Munich , Germany;2. Department of Environmental and Molecular Toxicology , Oregon State University , Corvallis , Oregon , USA;3. GenPharmTox BioTechAG , Martinsried , Germany |
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Abstract: | In human cells, the most carcinogenic polycyclic aromatic hydrocarbon dibenzo[ a,l ]pyrene (DB[ a,l ]P) forms high levels of DNA adducts through formation of the ( m )- anti -(11 R ,12 S )-diol (13 S ,14 R )-epoxide (DB[ a,l ]PDE) and its metabolic precursor, the ( m )-(11 R ,12 R )-diol. Generation of these adducts results from the catalytic activity of cytochrome P450 (P450) 1A1 and 1B1. Additional adducts such as (+)- syn -DB[ a,l ]PDE-DNA or more polar DNA adducts were detected only after increasing exposure doses of the parent compound or in cells that express P450 1A1. At low concentrations (·;100 nM) exclusively ( m )- anti -DB[ a,l ]PDE-DNA adducts were formed by P450 1B1, which is constitutively expressed in many mammalian tissues. Measurement of DNA binding and mutagenicity of DB[ a,l ]P in V79 cells expressing human P450 enzymes revealed a higher activity of P450 1B1 compared to 1A1 at low concentrations. Treatment of P450 1B1 knockout mice and DNA binding studies with fibroblasts isolated from these animals provided further evidence for the central role of P450 1B1-catalyzed formation of ( m )- anti -DB[ a,l ]PDE-DNA adducts in DB[ a,l ]P-induced carcinogenesis. |
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Keywords: | Carcinogenesis Dibenzo[ a,l ]pyrene Diol Epoxides Dna Adducts Knockout P450 1b1 |
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