Potent Mutagenicity of 3-Methylindole Requires Pulmonary Cytochrome P450-Mediated Bioactivation: A Comparison to the Prototype Cigarette Smoke Mutagens B(a)P and NNK
| Autor: | Jessica M. Weems, Garold S. Yost, Xinxin Ding, John G. Lamb, Jaime D'Agostino |
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| Rok vydání: | 2010 |
| Předmět: |
Ribosomal Proteins
Salmonella typhimurium Nitrosamines DNA damage Toxicology Article chemistry.chemical_compound Cytochrome P-450 Enzyme System Microsomes Benzo(a)pyrene Animals Humans Lung Cells Cultured Carcinogen biology Mutagenicity Tests Ribosomal Protein S9 Chemistry Smoking Mutagenesis Cytochrome P450 General Medicine Rats Skatole Comet assay CYP2A13 Liver Biochemistry biology.protein Microsome Aryl Hydrocarbon Hydroxylases DNA Damage Mutagens |
| Zdroj: | Chemical Research in Toxicology. 23:1682-1690 |
| ISSN: | 1520-5010 0893-228X |
| Popis: | 3-Methylindole (3MI) is a preferential pneumotoxicant found in cigarette smoke. A number of lung-expressed human cytochrome P450 enzymes, including 1A1, 2F1, and 2A13, catalyze the metabolism of 3MI to reactive intermediates that fragment DNA – measured with the Comet assay to assess DNA damage – in a cytochrome P450-dependent manner in primary normal human lung cells in culture, but the mutagenesis of 3MI has been controversial. In the present study, the mutagenic potential of 3MI was compared to the prototypical cigarette smoke carcinogens benzo(a)pyrene (B(a)P) and 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK). 3MI, B(a)P, and NNK were incubated with the Salmonella typhimurium strain TA98, which is known to detect the most common subtype of cigarette smoke-induced mutagenicity, frameshift mutations in DNA, and with Salmonella typhimurium strain TA100 which detects base pair substitution mutants, with five sources of P450-mediated bioactivation: rat liver S9, human lung microsomes, recombinant CYP2A13, purified CYP2F3, and recombinant CYP1A1. Only B(a)P was mutagenic in TA100 and it was bioactivated by human lung microsomes and rat liver S9 sources of P450s. However with the TA98 strain, CYP1A1, CYP2A13, CYP2F3, and human lung microsomes bioactivated 3MI to highly mutagenic intermediates, whereas neither human nor rat liver S9 sub-cellular fractions formed mutagenic intermediates from 3MI. Quantitative western blot analysis verified that all three respiratory enzymes were present in human lung microsomes in widely varying amounts. These results indicate that metabolism of 3MI by human lung-expressed cytochrome P450 enzymes, but not hepatic P450s, elicits equivalent or higher mutagenicity than the prototype cigarette smoke mutagens B(a)P and NNK and indicates that 3MI is a likely human pulmonary carcinogen. |
| Databáze: | OpenAIRE |
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