Pathobiological effects of aldehydes in cultured human bronchial cells.

Effects of the tobacco smoke-related aldehydes, i.e., acetaldehyde, formaldehyde and acrolein, have been investigated in cultured human bronchial epithelial cells and fibroblasts. As determined from loss of colony-forming efficiency of epithelial cells, acrolein is 200- and 5000-fold more toxic than formaldehyde and acetaldehyde, respectively. The aldehydes differ markedly in their potencies to induce terminal differentiation, as indicated by cessation of growth and enhanced formation of cross-linked envelopes. The cellular content of glutathione is markedly decreased by acrolein, whereas formaldehyde and acetaldehyde only slightly decrease glutathione levels. All three aldehydes produce DNA damage, as indicated by the formation of DNA single-strand breaks and DNA protein cross-links. Both formaldehyde and acrolein are weakly mutagenic in fibroblasts. In-vitro assays of O6-methylguanine-DNA methyltransferase (MMT) activity indicate that it is markedly inhibited by acrolein, and to a lesser extent by formaldehyde. However, formaldehyde significantly inhibits removal of O6-methylguanine (O6-meG) in N-methyl-N-nitrosourea (MNU)-exposed cells. Thus, the many biological effects induced by aldehydes include: inhibition of proliferation, enhanced cellular differentiation, thiol depletion, DNA damage, mutation and inhibition of DNA repair in human cells. Furthermore, we speculate that exogenous or metabolically generated aldehydes may increase the genotoxicity of N-nitroso compounds by the dual action of causing DNA damage and inhibiting the repair of promutagenic O6-meG DNA lesions in human cells.