We previously reported that tobacco smoke contains substances capable of binding iron in an aqueous medium and transferring the metal into organic solvents and intact mammalian red cells. Most, if not all, of this Fe binding activity was found to be due to free fatty acids (FFAs), primarily 16:0, 18:0, and 18:1, which are abundant in tobacco smoke. These earlier observations suggested that delocalization of Fe within the lung by smoke-borne FFAs might contribute to both the chronic pulmonary inflammation and carcinogenesis associated with smoking. We have therefore investigated the cytotoxic and mutagenic effects of micromolar amounts of FFAs and Fe on cultured human lung fibroblasts (immortalized by expression of telomerase). The results indicate that neither Fe nor FFA alone is cytotoxic in low concentrations. However, when combined, the same low concentrations of iron and FFA exert synergistic toxicity (following 24 hr exposure to 40 μM palmitic acid [PA] ± 20 μM ferric ammonium citrate, viability = 96 ± 3% [Fe alone], 95 ± 6% [PA alone] vs. 12 ± 18% [PA + Fe]). This toxicity coincides with a ˜ 5-fold increase in “loose” intracellular Fe. Furthermore, the combination of FFA and iron is highly mutagenic, inducing almost as many selectable mutations in the HGPRT gene as benzo[a]pyrene diolepoxide [BPDE], a class I carcinogen present in cigarette smoke (following 24 hr exposure to 50 μM PA + 25 μM Fe, 102 thioguanine resistant clones/106 cells vs. 175 clones/106 cells with 40 μM BPDE; background control = 11 clones/106 cells. The combination also promotes transformation of NIH 3T3 cells into an anchorage-independent phenotype (89 colonies/107 cells following 24 hr exposure to 50 μM PA + 25 μM Fe; for both untreated cells and cells exposed to 30 μM Fe alone, 0 colonies/107 cells. These results indicate that FFAs in tobacco smoke may be important contributors to both the pulmonary inflammation and carcinogenesis associated with smoking.
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