4-(Methylnitrosamino)-1-(3-pyridyl)-1-butanone (Synonyms: NNK) |
| رقم الكتالوجGC46607 |
4-(Methylnitrosamino)-1-(3-pyridyl)-1-butanone is a potent tobacco-specific carcinogen primarily found in tobacco products. It has a high affinity for α7 nicotinic acetylcholine receptors (α7 nAChR), with EC50 values of 0.03μM in small cell lung carcinoma (SCLCs) and 0.005μM in pulmonary neuroendocrine cells (PNECs).
Products are for research use only. Not for human use. We do not sell to patients.
Cas No.: 64091-91-4
Sample solution is provided at 25 µL, 10mM.
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4-(Methylnitrosamino)-1-(3-pyridyl)-1-butanone is a potent tobacco-specific carcinogen primarily found in tobacco products. It has a high affinity for α7 nicotinic acetylcholine receptors (α7 nAChR), with EC50 values of 0.03μM in small cell lung carcinoma (SCLCs) and 0.005μM in pulmonary neuroendocrine cells (PNECs)[1][2]. 4-(Methylnitrosamino)-1-(3-pyridyl)-1-butanone can induce the occurrence of tumors in various tissues, such as the lungs and liver. Studying its carcinogenic mechanisms helps to develop strategies for the prevention and treatment of tobacco-related cancers[3][4][5][6]. In tobacco harm reduction research, the content of 4-(Methylnitrosamino)-1-(3-pyridyl)-1-butanone and the levels of its metabolites are often used as important indicators for assessing safety[7].
In vitro, 4-(Methylnitrosamino)-1-(3-pyridyl)-1-butanone interacts with the α7 nAChR and activates the Raf-1/MAPK signaling cascade, promoting cancer progression and cancer cell proliferation. In cultured PNECs, a 6-day exposure to 100pM 4-(Methylnitrosamino)-1-(3-pyridyl)-1-butanone led to an 11.9-fold increase in Raf-1 protein and a 2.8-fold increase in MAPK protein. A single dose of 4-(Methylnitrosamino)-1-(3-pyridyl)-1-butanone (100pM) caused time-dependent increases in Raf-1 and MAPK proteins, peaking at 4.8-fold for Raf-1 at 5min and 2.9-fold for MAPK at 15min. PNEC showed significant increases in DNA synthesis in response to 100pM 4-(Methylnitrosamino)-1-(3-pyridyl)-1-butanone, peaking at 150min[2]. 4-(Methylnitrosamino)-1-(3-pyridyl)-1-butanone (100pM) incubation for 6 days induced proliferation of NCI-H69 lung cancer cells may occur through phosphorylation of Bcl2 and c-Myc to facilitate their cooperation[3]. In mono-culture system, 4-(Methylnitrosamino)-1-(3-pyridyl)-1-butanone (50, 100, and 200μg/mL) treatment for 24h decreased human bronchial epithelial cells (Beas-2B) proliferation, increased apoptosis, caused G1 phase arrest, and increased DNA damage in a dose-dependent manner. However, these cytotoxic effects were significantly reduced in the co-culture model of Beas-2B and macrophages cells (U937) in transwell, likely due to changes in cytokine expression and activation of related pathways[4].
In vivo, C3H and A/J mice were treated with three doses of 4-(Methylnitrosamino)-1-(3-pyridyl)-1-butanone (100mg/kg/d) via intraperitoneal injection on three alternate days. C3H mice did not develop noticeable lung tumors within 7 months after 4-(Methylnitrosamino)-1-(3-pyridyl)-1-butanone treatment. In contrast, A/J mice developed visible lung tumors with an adenomatous pattern. Their immune responses were significantly suppressed, including AFC response, and anti-CD3/CD28 antibody-induced intracellular calcium concentration changes. Moreover, 4-(Methylnitrosamino)-1-(3-pyridyl)-1-butanone treatment led to a sustained increase in the expression of α7-nAChR and COX-2 in the lungs of A/J mice[5]. 4-(Methylnitrosamino)-1-(3-pyridyl)-1-butanone was administered to A/J mice in the drinking water during 7 weeks at doses of 9.2 or 3.1mg/mouse. Mice that received a total dose of 9.2mg 4-(Methylnitrosamino)-1-(3-pyridyl)-1-butanone per mouse had an average of 15.7 ± 2.7 lung tumors, whereas those that received 3.1mg 4-(Methylnitrosamino)-1-(3-pyridyl)-1-butanone per mouse had only 1.2 ± 0.3 tumors per mouse[6]. Male ICR mice were exposed to 4-(Methylnitrosamino)-1-(3-pyridyl)-1-butanone (0.5mg/mouse) and sodium arsenite (0, 10, or 20mg/kg) daily via gavaging for 10 days and their urine was collected at day 10 for 4-(Methylnitrosamino)-1-(3-pyridyl)-1-butanone metabolite analysis. The results suggested that sodium arsenite increased 4-(Methylnitrosamino)-1-(3-pyridyl)-1-butanone metabolism by up-regulation of CYP2A expression and activity leading to an increased 4-(Methylnitrosamino)-1-(3-pyridyl)-1-butanone metabolism and DNA adducts[7].
References:
[1] Lisa A Peterson L A, Stephen B Stanfill S B, Stephen S Hecht S S. An update on the formation in tobacco, toxicity and carcinogenicity of N'-nitrosonornicotine and 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone. Carcinogenesis. 2024 May 19;45(5):275-287.
[2] Schuller H M, Plummer H K, Jull B A. Receptor-mediated effects of nicotine and its nitrosated derivative NNK on pulmonary neuroendocrine cells. Anat Rec A Discov Mol Cell Evol Biol. 2003 Jan;270(1):51-8.
[3] Jin Z H, Gao F Q, Flagg T, Deng X M. Tobacco-specific nitrosamine 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone promotes functional cooperation of Bcl2 and c-Myc through phosphorylation in regulating cell survival and proliferation. J Biol Chem. 2004 Sep 17;279(38):40209-19.
[4] Zhou J X, Zou H X, Liu Y Q, et al. Acute cytotoxicity test of PM2.5, NNK and BPDE in human normal bronchial epithelial cells: A comparison of a co-culture model containing macrophages and a mono-culture model. Toxicol In Vitro. 2022 Dec:85:105480.
[5] Boroujerdi R S, Sopori M L. Early manifestations of NNK-induced lung cancer: role of lung immunity in tumor susceptibility. Am J Respir Cell Mol Biol. 2007 Jan;36(1):13-9.
[6] Castonguay A, Pepin P, Stoner G D.Lung tumorigenicity of NNK given orally to A/J mice: its application to chemopreventive efficacy studies. Exp Lung Res. 1991 Mar-Apr;17(2):485-99.
[7] Lee H L, Chang L W, Wu J P, et al. Enhancements of 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (4-(Methylnitrosamino)-1-(3-pyridyl)-1-butanone) metabolism and carcinogenic risk via 4-(Methylnitrosamino)-1-(3-pyridyl)-1-butanone/arsenic interaction. Toxicol Appl Pharmacol. 2008 Feb 15;227(1):108-14.
| Cell experiment [1]: | |
|
Cell lines |
human bronchial epithelial cells (Beas-2B) |
|
Preparation Method |
First, macrophages cells (U937) were treated with PMA (Phorbol-12-myristate 13-acetate) for 24h to induce differentiation into macrophage-like cells. Beas-2B cells were cultured in the lower room of the (1.2 × 105 cells/well) transwell system. Beas-2B cells grown in mono-culture or co-culture systems with U937 were observed respectively under the microscopy after 4-(Methylnitrosamino)-1-(3-pyridyl)-1-butanone exposure for 24h to better understand its effects on cell growth, adhesion and morphology. |
|
Reaction Conditions |
50, 100 and 200μg/mL; 24h |
|
Applications |
In mono-culture system, 4-(Methylnitrosamino)-1-(3-pyridyl)-1-butanone decreased human bronchial epithelial cells (Beas-2B) proliferation, increased apoptosis, caused G1 phase arrest, and increased DNA damage in a dose-dependent manner. However, these cytotoxic effects were significantly reduced in the co-culture model of Beas-2B and macrophages cells (U937) in transwell, likely due to changes in cytokine expression and activation of related pathways. |
| Animal experiment [2]: | |
|
Animal models |
C3H and A/J mice |
|
Preparation Method |
Mice were injected intraperitoneally with three doses of 4-(Methylnitrosamino)-1-(3-pyridyl)-1-butanone (100mg/kg/d in 0.1ml PBS) on three alternate days. Control animals received an equivalent volume of PBS. |
|
Dosage form |
100mg/kg/d; i.p.; 3 times |
|
Applications |
C3H mice did not develop noticeable lung tumors within 7 months after 4-(Methylnitrosamino)-1-(3-pyridyl)-1-butanone treatment. In contrast, A/J mice developed visible lung tumors with an adenomatous pattern. Their immune responses were significantly suppressed, including AFC response, and anti-CD3/CD28 antibody-induced intracellular calcium concentration changes. Moreover, 4-(Methylnitrosamino)-1-(3-pyridyl)-1-butanone treatment led to a sustained increase in the expression of α7-nAChR and COX-2 in the lungs of A/J mice. |
|
References: |
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| Cas No. | 64091-91-4 | SDF | |
| المرادفات | NNK | ||
| Canonical SMILES | O=C(CCCN(C)N=O)C1=CC=CN=C1 | ||
| Formula | C10H13N3O2 | M.Wt | 207.2 |
| الذوبان | DMF: 30 mg/ml, DMSO: 25 mg/ml, Ethanol: 25 mg/ml, | Storage | Store at -20°C |
| General tips | Please select the appropriate solvent to prepare the stock solution according to the
solubility of the product in different solvents; once the solution is prepared, please store it in
separate packages to avoid product failure caused by repeated freezing and thawing.Storage method
and period of the stock solution: When stored at -80°C, please use it within 6 months; when stored
at -20°C, please use it within 1 month. To increase solubility, heat the tube to 37°C and then oscillate in an ultrasonic bath for some time. |
||
| Shipping Condition | Evaluation sample solution: shipped with blue ice. All other sizes available: with RT, or with Blue Ice upon request. | ||
| Prepare stock solution | |||
|
1 mg | 5 mg | 10 mg |
| 1 mM | 4.8263 mL | 24.1313 mL | 48.2625 mL |
| 5 mM | 965.3 μL | 4.8263 mL | 9.6525 mL |
| 10 mM | 482.6 μL | 2.4131 mL | 4.8263 mL |
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- Purity: >98.00%
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