Inhibition of N-diethylnitrosamine metabolism by human lung cancer cell lines with features of well differentiated pulmonary endocrine cells.
Cell lines derived from a human pulmonary carcinoid tumor (NCI-H727) and from a human pulmonary large cell carcinoma (NCI-H460) were investigated by transmission electron microscopy. Both cell lines, at early in vitro passage, demonstrated ultrastructural features of well differentiated pulmonary endocrine cells. Line NCI-H727 had more endoplasmic reticulum than line NCI-H460 and demonstrated L-dopa decarboxylase activity as well as production of calcitonin and bombesin. Because of their ultrastructural resemblance with normal pulmonary endocrine cells, these cell lines were used to test the theory derived from experiments in hamsters that human pulmonary endocrine cells can metabolize N-nitrosodiethylamine (DEN). The cells were incubated in vitro with [14C]DEN. Metabolism was assessed by 14CO2 production. Both cell lines metabolized DEN to a much greater extent than previously investigated human lung cancer cell lines of Clara cell and alveolar type II cell morphology. In keeping with its abundant endoplasmic reticulum, line NCI-H727 yielded 14CO2 in the 300 nM range, whereas NCI-H460 was less active. Metabolism was time dependent. Preincubation with various enzyme inhibitors yielded a highly significant inhibition of DEN metabolism with the two inhibitors of the fatty acid cyclooxygenase component of prostaglandin endoperoxide synthetase, aspirin and indomethacin. Inhibitors of cytochrome P-450 (CO, piperoxylbutoxide) did not inhibit DEN metabolism. Preincubation with sinigrin yielded similar negative results as CO and piperonylbutoxide. Our data are in support of the theory that human pulmonary endocrine cells can metabolize nitrosamines. Moreover, the experiments with enzyme inhibitors suggest that in this cell type such metabolism is largely dependent on prostaglandin endoperoxide synthetase.