Nitrosamines as nicotinic receptor ligands.

摘要: Nitrosamines are carcinogens formed in the mammalian organism from amine precursors contained food, beverages, cosmetics and drugs. The potent carcinogen, NNK, weaker NNN, nitrosamines nicotine. Metabolites of react with DNA to form adducts responsible for genotoxic effects. We have identified NNK as a high affinity agonist alpha7 nicotinic acetylcholine receptor (alpha7nAChR) whereas NNN bound epibatidine-sensitive nAChRs. Diethylnitrosamine (DEN) both receptors but lower affinity. High levels alpha7nAChR were expressed human small cell lung cancer (SCLC) lines hamster pulmonary neuroendocrine cells (PNECs), which serve model origin SCLC. Exposure SCLC or PNECs nicotine increased expression caused influx Ca(2+), activation PKC, Raf-1, ERK1/2, c-myc, resulting stimulation proliferation. Signaling via was enhanced when maintained an environment 10-15% CO(2) similar that diseased lung. Hamsters hyperoxia-induced fibrosis developed carcinomas treated DEN, development NNK-induced tumors prevented by green tea theophylline. beta-adrenergic agonist, isoproterenol theophylline blocked proliferation vitro. nicotine-induced hyperactivity alpha7nAChR/RAF/ERK1/2 pathway thus appears play crucial role smokers could be targeted prevention.