Metabolic Activation of Polycyclic Aromatic Hydrocarbons and Aryl and Heterocyclic Amines by Human Cytochromes P450 2A13 and 2A6
-
- Tsutomu Shimada
- Department of Biochemistry and Center in Molecular Toxicology, Vanderbilt University School of Medicine, Nashville, Tennessee 37232-0146, United States
-
- Norie Murayama
- Laboratory of Drug Metabolism and Pharmacokinetics, Showa Pharmaceutical University, Machida, Tokyo 194-8543, Japan
-
- Hiroshi Yamazaki
- Laboratory of Drug Metabolism and Pharmacokinetics, Showa Pharmaceutical University, Machida, Tokyo 194-8543, Japan
-
- Katsuhiro Tanaka
- Laboratory of Cellular and Molecular Biology, Graduate School of Life and Environmental Sciences, Osaka Prefecture University, 1-58 Rinku-Orai-Kita, Izumisano, Osaka 598-8531, Japan
-
- Shigeo Takenaka
- Laboratory of Cellular and Molecular Biology, Graduate School of Life and Environmental Sciences, Osaka Prefecture University, 1-58 Rinku-Orai-Kita, Izumisano, Osaka 598-8531, Japan
-
- Masayuki Komori
- Laboratory of Cellular and Molecular Biology, Graduate School of Life and Environmental Sciences, Osaka Prefecture University, 1-58 Rinku-Orai-Kita, Izumisano, Osaka 598-8531, Japan
-
- Donghak Kim
- Department of Biochemistry and Center in Molecular Toxicology, Vanderbilt University School of Medicine, Nashville, Tennessee 37232-0146, United States
-
- F. Peter Guengerich
- Department of Biochemistry and Center in Molecular Toxicology, Vanderbilt University School of Medicine, Nashville, Tennessee 37232-0146, United States
書誌事項
- 公開日
- 2013-03-13
- 資源種別
- journal article
- DOI
-
- 10.1021/tx3004906
- 公開者
- American Chemical Society (ACS)
この論文をさがす
説明
Human cytochrome P450 (P450) 2A13 was found to interact with several polycyclic aromatic hydrocarbons (PAHs) to produce Type I binding spectra, including acenaphthene, acenaphthylene, benzo[c]phenanthrene, fluoranthene, fluoranthene-2,3-diol, and 1-nitropyrene. P450 2A6 also interacted with acenaphthene and acenaphthylene, but not with fluoranthene, fluoranthene-2,3-diol, or 1-nitropyrene. P450 1B1 is well-known to oxidize many carcinogenic PAHs, and we found that several PAHs (i.e., 7,12-dimethylbenz[a]anthracene, 7,12-dimethylbenz[a]anthracene-5,6-diol, benzo[c]phenanthrene, fluoranthene, fluoranthene-2,3-diol, 5-methylchrysene, benz[a]pyrene-4,5-diol, benzo[a]pyrene-7,8-diol, 1-nitropyrene, 2-aminoanthracene, 2-aminofluorene, and 2-acetylaminofluorene) interacted with P450 1B1, producing Reverse Type I binding spectra. Metabolic activation of PAHs and aryl- and heterocyclic amines to genotoxic products was examined in Salmonella typhimurium NM2009, and we found that P450 2A13 and 2A6 (as well as P450 1B1) were able to activate several of these procarcinogens. The former two enzymes were particularly active in catalyzing 2-aminofluorene and 2-aminoanthracene activation, and molecular docking simulations supported the results with these procarcinogens, in terms of binding in the active sites of P450 2A13 and 2A6. These results suggest that P450 2A enzymes, as well as P450 Family 1 enzymes including P450 1B1, are major enzymes involved in activating PAHs and aryl- and heterocyclic amines, as well as tobacco-related nitrosamines.
収録刊行物
-
- Chemical Research in Toxicology
-
Chemical Research in Toxicology 26 (4), 529-537, 2013-03-13
American Chemical Society (ACS)
