Toxicokinetic and Genotoxicity Study of NNK in Male Sprague Dawley Rats Following Nose-Only Inhalation Exposure, Intraperitoneal Injection, and Oral Gavage
| Autor: | Steven B Yee, Wei Ding, Mason G. Pearce, Shu-Chieh Hu, Roberta A. Mittelstaedt, Raul A. Trbojevich, Susan Chemerynski, Melis Coraggio, R. Philip Yeager, Sherry M. Lewis, Hans Rosenfeldt, Yunan Tang, Guy Lagaud, Kelly Davis, Matthew Bryant, Estatira Sepehr, Michelle E. Bishop, Darshan Mehta, Hyun-Ki Kang, Paul C. Howard |
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| Rok vydání: | 2021 |
| Předmět: |
0301 basic medicine
Male Nitrosamines medicine.medical_treatment Intraperitoneal injection Pharmacology Toxicology medicine.disease_cause 01 natural sciences Rats Sprague-Dawley 03 medical and health sciences chemistry.chemical_compound Tandem Mass Spectrometry DNA adduct medicine Toxicokinetics Animals Carcinogen Chromatography High Pressure Liquid Inhalation exposure Inhalation Exposure Inhalation Chemistry 010401 analytical chemistry Rats Inbred F344 0104 chemical sciences Rats 030104 developmental biology Nitrosamine Carcinogens Genotoxicity Injections Intraperitoneal DNA Damage |
| Zdroj: | Toxicological sciences : an official journal of the Society of Toxicology. 182(1) |
| ISSN: | 1096-0929 |
| Popis: | The tobacco-specific nitrosamine NNK [4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone] is found in tobacco products and tobacco smoke. NNK is a potent genotoxin and human lung carcinogen; however, there are limited inhalation data for the toxicokinetics (TK) and genotoxicity of NNK in vivo. In the present study, a single dose of 5 × 10−5, 5 × 10−3, 0.1, or 50 mg/kg body weight (BW) of NNK, 75% propylene glycol (vehicle control), or air (sham control) was administered to male Sprague-Dawley (SD) rats (9–10 weeks age) via nose-only inhalation (INH) exposure for 1 h. For comparison, the same doses of NNK were administered to male SD rats via intraperitoneal injection (IP) and oral gavage (PO). Plasma, urine, and tissue specimens were collected at designated time points and analyzed for levels of NNK and its major metabolite 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol (NNAL) and tissue levels of DNA adduct O6-methylguanine by LC/MS/MS. TK data analysis was performed using a non-linear regression program. For the genotoxicity subgroup, tissues were collected at 3 h post-dosing for comet assay analysis. Overall, the TK data indicated that NNK was rapidly absorbed and metabolized extensively to NNAL after NNK administration via the three routes. The IP route had the greatest systemic exposure to NNK. NNK metabolism to NNAL appeared to be more efficient via INH than IP or PO. NNK induced significant increases in DNA damage in multiple tissues via the three routes. The results of this study provide new information and understanding of the TK and genotoxicity of NNK. |
| Databáze: | OpenAIRE |
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