Tobacco-specific nitrosamines mediated phospholipid alterations by enhanced phospholipase A2 and acyltransferase activity in yeast and mammalian system

Abstract

The present study is the first report of 4-(methyl nitrosamino)-1-(3-pyridyl)-1- butanone (NNK) and N-nitrosonornicotine (NNN) on phospholipid metabolism using two different model systems. Tobacco specific nitrosamines (TSNAs) namely NNK and NNN are potent pulmonary carcinogens present in cigarette smoke and carcinogenicity of these compounds is very well documented. However the impact on lipid metabolism remains enigmatic, since NNK and NNN primarily target the respiratory system and respiratory function is fully dependent on lipid-protein complex called surfactant. Hence the present study was undertaken to investigate the impact of NNK and NNN on phospholipid metabolism. We initiated our objectives with Saccharomyces cerevisiae, a good model system for characterizing phospholipid metabolism. We observed reduced phospholipid content accompanied with enhanced phospholipase B (PLB), particularly plb1p activity with NNK (Vijayaraj et al., 2011b) and NNN (Vijayaraj et al., 2011a) exposure. The results have led us to investigate and confirm these changes in rat pulmonary surfactant metabolism. NNK and NNN primarily target the respiratory system and respiratory function is fully dependent on lipid-protein complex called surfactant. The phospholipids were reduced significantly due to enhanced deacylation by different form of phospholipase A2s (PLA2s) and they prefer to hydrolyse PC and PG in the presence of NNN and NNK respectively. NNK and NNN increased the expression of secretory PLA2s (sPLA2- IIA and sPLA2-V) and lysosomal- PLA2 (LPLA2) in alveolar epithelial type 2 cells (AEC2). Further both NNK and NNN significantly enhanced acyltransferases, LPCAT and LPGAT activity and also induces the expression of LPCAT and LPGAT. Remodelling enzyme reduced dipalmitoyl phosphatidylcholine (DPPC) formation accompanied with increase of other fatty acids, mainly arachidonic acid (AA) in AEC2 exposed to NNK and NNN.