TOBACCO-BORNE IRON-BINDING SUBSTANCES

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Many pathologic processes are exacerbated by iron. These may include the chronic inflammation, progressive pulmonary damage and predisposition to neoplasia seen in smokers. Indeed, the lungs of long-term smokers tend to accumulate abnormally large amounts of iron for unknown reasons. We have tested extracts of tobacco and tobacco smoke for substances which might bind and, especially, translocate iron across cell membranes. We find materials in tobacco and tobacco smoke which cause the solvation of iron in non-polar organic solvents such as chloroform and also cause intact human cells to accumulate iron. These substances have been purified and identified as free fatty acids (previously identified as major constituents of tobacco smoke), and pure fatty acids duplicate the iron-translating effects of smoke condensates and tobacco extracts. Unexpectedly, we also find that such free fatty acids directly stimulate hypochlorous acid production by human neutrophils and can double the output of hypochlorous acid by phorbol myristate acetate stimulated neutrophils. The proposed work is aimed at further definition of the importance of iron delocalization, and of free fatty acids per se in the genesis of smoking-related diseases. Specifically: (1) We shall determine the effectiveness of smoke condensates and free fatty acids in delivering iron into whole cells (using human red cells as a model and cultured endothelial and pulmonary epithelial cells as more realistic targets). (2) We shall define the effects of free fatty acids and fatty acid-mediated iron loading on neutrophil function, the oxidation of lipids in target cell membranes and on oxidative destruction of iron-loaded target cells by oxidants of reagent, enzymatic and phagocytic origin. (3) We shall also determine whether this 'delocalization' of iron might play a part in the carcinogenic activities of cigarette smoke, especially through exerting either clastogenic or (through non-transferrin-dependent iron delivery) growth-promoting effects. (4) Finally, limited investigations are planned to examine the consequences of long term exposure of animals to volatilized free fatty acids. It is hoped that knowledge of the cellular effects of inhaled free fatty acids will help elucidate the pathogenesis of smoking-related disorders and might lead to the development of strategies to minimize or reverse some of the pathologic effects of long-term tobacco use.