The influence of tobacco smoke/nicotine on CYP2A expression in human and African green monkey lungs
| Autor: | Yuan Gao, Roberta M. Palmour, Rachel F. Tyndale, Sharon Miksys |
|---|---|
| Rok vydání: | 2020 |
| Předmět: |
Male
0301 basic medicine Nicotine medicine.medical_specialty Lung Neoplasms Datasets as Topic Tobacco smoke 03 medical and health sciences 0302 clinical medicine Smoke Internal medicine Chlorocebus aethiops Tobacco Animals Humans Medicine RNA Messenger CYP2A6 Lung cancer Lung Pharmacology Messenger RNA Smokers Sequence Analysis RNA business.industry Gene Expression Profiling Smoking CYP1A2 Non-Smokers respiratory system medicine.disease respiratory tract diseases Disease Models Animal 030104 developmental biology medicine.anatomical_structure CYP2A13 Endocrinology Steroid Hydroxylases Microsomes Liver Molecular Medicine Tobacco Smoke Pollution Aryl Hydrocarbon Hydroxylases business 030217 neurology & neurosurgery medicine.drug |
| DOI: | 10.22541/au.159285510.07118043 |
| Popis: | CYP2A enzymes metabolically inactivate nicotine and activate tobacco-derived procarcinogens [e.g., 4-[methylnitrosamino]-1-(3-pyridyl)-1-butanone]. Smoking decreases nicotine clearance, and chronic nicotine reduces hepatic CYP2A activity. However, little is known about the impact of smoking or nicotine on the expression of CYP2A in the lung. We investigated 1) the levels of human lung CYP2A mRNA in smokers versus nonsmokers and 2) the impact of daily nicotine treatment on lung CYP2A protein levels in African green monkeys (AGMs). Lung CYP2A13, CYP2A6, and CYP2A7 (and CYP1A2) mRNA levels in smokers and nonsmokers were assessed in Gene Expression Omnibus data sets (GSE30063, GSE108134, and GSE11784). The impact of chronic, twice-daily, subcutaneous nicotine at two doses (0.3 and 0.5 mg/kg) versus vehicle on lung CYP2A protein levels was assessed. The impact of ethanol self-administration was also investigated, with and without nicotine treatment. Smokers versus nonsmokers (from GSE30063 and GSE108134) had lower (1.04- to 1.12-fold) levels of lung CYP2A13, CYP2A6, and CYP2A7 (and higher CYP1A2) mRNA. Both doses of nicotine tested decreased AGM lung CYP2A protein (3- to 7-fold). Ethanol self-administration had no effect on AGM lung CYP2A protein, and there was no interaction between ethanol and nicotine. Our results suggest that smoking was associated with a reduction in human lung CYP2A13, CYP2A6, and CYP2A7 mRNA, consistent with the role of nicotine treatment in reducing AGM lung CYP2A protein. This regulation by smoking/nicotine will increase interindividual variation in lung CYP2A levels, which may impact the localized metabolism of inhaled drugs and tobacco smoke procarcinogens. SIGNIFICANCE STATEMENT: CYP2A13 and CYP2A6 are expressed in the lung and may contribute to local procarcinogen activation. Smokers had lower lung CYP2A mRNA levels compared with nonsmokers. Lung CYP2A protein expression was decreased by systemic treatment with nicotine. Decreased lung CYP2A expression may alter smoking-related lung cancer risk and tissue damage from other inhaled toxins. This novel regulatory impact of nicotine, including nicotine found in smoking-cessation nicotine-replacement therapies, may have potential benefits on smoking-related lung cancer risk. |
| Databáze: | OpenAIRE |
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