Cell type-specific differences in metabolic activation of N-nitrosodiethylamine by human lung cancer cell lines

The metabolism of N-nitrosodiethylamine (NDEA) and its modulation by inhibitors of cytochrome P450 and prostaglandin H synthetase enzymes was investigated in seven well-differentiated early-passage human lung cancer cell lines. NDEA metabolism was assessed by covalent binding and evolution of carbon dioxide. Morphological diagnosis of cell lines was done by light and electron microscopy. Two cell lines (NCI-H69, NCI-H128) with characteristics of small-cell cancer did not metabolize NDEA. Two cells lines (NCI-H322) with features of adenocarcinoma, comprised of Clara cells, and (NCI-H727), with features of pulmonary endocrine cells, were more potent than all other cell lines in metabolizing NDEA. A cell line divided from an adenocarcinoma but comprised of alveolar type-II cells (NCI-H358) metabolized NDEA predominantly via prostaglandin H synthetase. Similarly, several cell lines with features of well-differentiated pulmonary endocrine cells (NCI-H727, NCI-H460) metabolized NDEA via prostaglandin H synthetase, while the cell line comprised of Clara cells (NCI-H322) activated the nitrosamine by cytochrome P450 but not by prostaglandin H synthetase. Although cancer cells may react differently from normal cells to xenobiotics, our data provide substantial evidence for the hypothesis that--as in the hamster--Clara cells and pulmonary endocrine cells are potential major targets of NDEA carcinogenesis in human lung. It is of particular interest that different cell types activate the nitrosamine via different enzyme systems.