Acrolein Increases the Pulmonary Tumorigenic Activity of the Tobacco-Specific Nitrosamine 4-(Methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK)

Abstract

Tobacco smoke is a complex mixture of more than 7000 chemicals, of which many are toxic and/or carcinogenic. Many hazard assessments of tobacco have focused on individual chemical exposures without consideration of how the chemicals may interact with one another. Two chemicals, the human carcinogen 4-methylnitrosamino-1-(3-pyridyl)-1-butanone (NNK) and a possible human carcinogen, acrolein, were hypothesized to interact with one another, possibly owing to the additive effects of DNA adduct formation or influence on the repair of mutagenic DNA adducts. To test our hypothesis that coexposure to NNK and acrolein is more carcinogenic than either chemical alone, A/J mice were exposed to NNK (i.p., 0, 2.5, or 7.5 μmol in saline) in the presence or absence of inhaled acrolein (15 ppmV). While the single 3 h exposure to acrolein alone did not induce lung adenomas, it significantly enhanced NNK's lung carcinogenicity. In addition, mice receiving both NNK and acrolein had more adenomas with dysplasia or progression than those receiving only NNK, suggesting that acrolein may also increase the severity of NNK-induced lung adenomas. To test the hypothesis that the interaction was due to effects on DNA adduct formation and repair, NNK-and acrolein pulmonary DNA adduct levels were assessed. There was no consistent effect of the coexposure on NNK-derived DNA adducts, and acrolein DNA adducts were not elevated above endogenous levels. This study supports the hypothesis that tobacco smoke chemicals combine to contribute to the carcinogenic potency of tobacco smoke, and the mechanism of interaction cannot be explained by alterations of DNA adduct levels.

The Tobacco Smoke Component, Acrolein, as a Major Culprit in Lung Diseases and Respiratory Cancers: Molecular Mechanisms of Acrolein Cytotoxic Activity

“…Acrolein, a component of cigarette smoke, is considered one of the main risk factors for lung cancer [ 68 ]. Notably, as indicated by Peterson et al [ 159 ] in the latest research, although acrolein itself is a potent mutagen, it can also synergize with other compounds present in cigarette smoke. Acrolein has been proven to increase the pulmonary tumorigenic activity of the nitrosamine 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK).…”

“…Three-hour incubation of mice on acrolein did not induce lung adenomas, whereas it did significantly enhance NNK’s lung carcinogenicity; however, the mechanism of this interaction is unclear. Research undoubtedly provides valuable information that tobacco smoke chemicals are more active in a mixture, and that the complex interactions between them increase tobacco smoke’s strong carcinogenic properties [ 159 ].…”

Diet as a Source of Acrolein: Molecular Basis of Aldehyde Biological Activity in Diabetes and Digestive System Diseases

“…This fact is unsurprising because cigarettes and tobacco products (including e-cigarettes) are one of the main sources of human exposure to this aldehyde. It should be emphasized that acrolein, as a compound with very high reactivity, is extremely toxic in itself, and in addition, it can enhance the toxic effects of other mutagens present in cigarette smoke, e.g., polycyclic aromatic hydrocarbons (PAHs) [ 142 ]. In addition, as indicated by recent studies by Hong et al, acrolein, by affecting the HER2/FGFR3 signaling pathways, may contribute to reducing the effectiveness of conventional chemotherapy in the treatment of bladder cancer.…”