Abstract
4-(Methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) is a potent lung carcinogen present in tobacco products, and exposure to it is likely one of the factors contributing to the development of lung cancer in cigarette smokers. To exert its carcinogenic effects, NNK must be metabolically activated into highly reactive species generating a wide spectrum of DNA damage. We have identified a new class of DNA adducts, DNA-RNA cross-links found for the first time in NNK-treated mice lung DNA using our improved high-resolution accurate mass segmented full scan data-dependent neutral loss MS3screening strategy. The levels of these DNA-RNA cross-links were found to be significantly higher in NNK-treated mice compared to the corresponding controls, which is consistent with higher levels of formaldehyde due to NNK metabolism as compared to endogenous levels. We hypothesize that this DNA-RNA cross-linking occurs through reaction with NNK-generated formaldehyde and speculate that this phenomenon has broad implications for NNK-induced carcinogenesis. The structures of these cross-links were characterized using high-resolution LC-MS2and LC-MS3accurate mass spectral analysis and comparison to a newly synthesized standard. Taken together, our data demonstrate a previously unknown link between DNA-RNA cross-link adducts and NNK and provide a unique opportunity to further investigate how these novel NNK-derived DNA-RNA cross-links contribute to carcinogenesis in the future.
| Original language | English (US) |
|---|---|
| Pages (from-to) | 2025-2036 |
| Number of pages | 12 |
| Journal | Chemical research in toxicology |
| Volume | 35 |
| Issue number | 11 |
| DOIs | |
| State | Published - Nov 21 2022 |
Bibliographical note
Funding Information:This work was supported by the U.S. National Institute of Health and National Cancer Institute [NCI-CA220376] and by contribution from the Renville County Walk in the Park and Pages of Our Community Foundation. Mass spectrometry was carried out in the Analytical Biochemistry Shared Resource of the Masonic Cancer Center, supported in part by the U.S. National Institute of Health and National Cancer Institute [Cancer Center Support Grant CA-77598]. Salary support for P.W.V. was provided by the National Cancer Institute (Grant No. R50-CA211256). H.D.N. is a EvansMDS Young Investigator (Edward P. Evans Foundation) and an ASH Scholar (American Society of Hematology). H.D.N. is supported by the National Institutes of Health’s National Center for Advancing Translational Sciences, Grant Nos. KL2TR002492 and UL1TR002494, and National Heart, Lung, and Blood Institute, R01HL163011. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health’s National Center for Advancing Translational Sciences. We thank Prof. Kassie’s group for assistance in the animal experiment, Laura A. Maertens, and Andrew C. Floeder for the DNA extraction. Finally, we thank Dr. Todd Rappe from the Minnesota NMR Center for support with the NMR spectra acquisition.
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