-
Tytuł:
-
Toxicokinetic and Genotoxicity Study of NNK in Male Sprague Dawley Rats Following Nose-Only Inhalation Exposure, Intraperitoneal Injection, and Oral Gavage.
-
Autorzy:
-
Hu SC; National Center for Toxicological Research (NCTR), U.S. Food and Drug Administration (FDA), Jefferson, AR 72079.
Bryant MS; National Center for Toxicological Research (NCTR), U.S. Food and Drug Administration (FDA), Jefferson, AR 72079.
Sepehr E; National Center for Toxicological Research (NCTR), U.S. Food and Drug Administration (FDA), Jefferson, AR 72079.
Kang HK; National Center for Toxicological Research (NCTR), U.S. Food and Drug Administration (FDA), Jefferson, AR 72079.
Trbojevich R; National Center for Toxicological Research (NCTR), U.S. Food and Drug Administration (FDA), Jefferson, AR 72079.
Lagaud G; The Center for Tobacco Products (CTP), U.S. Food and Drug Administration, Silver Spring, MD 20993, USA.
Mehta D; National Center for Toxicological Research (NCTR), U.S. Food and Drug Administration (FDA), Jefferson, AR 72079.
Ding W; National Center for Toxicological Research (NCTR), U.S. Food and Drug Administration (FDA), Jefferson, AR 72079.
Mittelstaedt RA; National Center for Toxicological Research (NCTR), U.S. Food and Drug Administration (FDA), Jefferson, AR 72079.
Pearce MG; National Center for Toxicological Research (NCTR), U.S. Food and Drug Administration (FDA), Jefferson, AR 72079.
Bishop ME; National Center for Toxicological Research (NCTR), U.S. Food and Drug Administration (FDA), Jefferson, AR 72079.
Davis KJ; Toxicologic Pathology Associates, National Center for Toxicological Research, Jefferson, AR 72079, USA.
Lewis SM; National Center for Toxicological Research (NCTR), U.S. Food and Drug Administration (FDA), Jefferson, AR 72079.
Chemerynski S; The Center for Tobacco Products (CTP), U.S. Food and Drug Administration, Silver Spring, MD 20993, USA.
Yee SB; The Center for Tobacco Products (CTP), U.S. Food and Drug Administration, Silver Spring, MD 20993, USA.
Coraggio M; The Center for Tobacco Products (CTP), U.S. Food and Drug Administration, Silver Spring, MD 20993, USA.
Rosenfeldt H; The Center for Tobacco Products (CTP), U.S. Food and Drug Administration, Silver Spring, MD 20993, USA.
Yeager RP; The Center for Tobacco Products (CTP), U.S. Food and Drug Administration, Silver Spring, MD 20993, USA.
Howard PC; National Center for Toxicological Research (NCTR), U.S. Food and Drug Administration (FDA), Jefferson, AR 72079.
Tang Y; National Center for Toxicological Research (NCTR), U.S. Food and Drug Administration (FDA), Jefferson, AR 72079.
-
Źródło:
-
Toxicological sciences : an official journal of the Society of Toxicology [Toxicol Sci] 2021 Jul 16; Vol. 182 (1), pp. 10-28.
-
Typ publikacji:
-
Journal Article; Research Support, U.S. Gov't, Non-P.H.S.
-
Język:
-
English
-
Imprint Name(s):
-
Publication: 1999- : Cary, NC : Oxford University Press
Original Publication: Orlando, FL : Academic Press, c1998-
-
MeSH Terms:
-
Nitrosamines*/toxicity
Tandem Mass Spectrometry*
Animals ; Carcinogens ; Chromatography, High Pressure Liquid ; DNA Damage ; Inhalation Exposure ; Injections, Intraperitoneal ; Male ; Rats ; Rats, Inbred F344 ; Rats, Sprague-Dawley ; Toxicokinetics
-
Grant Information:
-
United States FD FDA HHS; FDA; Center for Tobacco Products
-
Contributed Indexing:
-
Keywords: NNK; genotoxicity; intraperitoneal injection; nose-only inhalation exposure; oral gavage; toxicokinetic
-
Substance Nomenclature:
-
0 (Carcinogens)
0 (Nitrosamines)
-
Entry Date(s):
-
Date Created: 20210504 Date Completed: 20210818 Latest Revision: 20210818
-
Update Code:
-
20240104
-
DOI:
-
10.1093/toxsci/kfab049
-
PMID:
-
33944952
-
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.
(Published by Oxford University Press on behalf of the Society of Toxicology 2021. This work is written by US Government employees and is in the public domain in the US.)
