Smokeless Tobacco-Associated Nitrosamines Impact on Aryl Hydrocarbon Receptor: In Silico and In Vitro Study.
5 affiliations
- 1Division of Molecular Genetics and Biochemistry, Molecular Biology Group, ICMR-National Institute of Cancer Prevention and Research, Noida, Uttar Pradesh, India.
- 2Department of Biotechnology, School of Engineering and Technology, Noida International University, Greater Noida, Uttar Pradesh, India.
- 3School of Biotechnology, Gautam Buddha University, Greater Noida, Uttar Pradesh, India.
- 4Molecular Biology Group, ICMR-National Institute of Cancer Prevention and Research, Noida, Uttar Pradesh, India.
- 5Academy of Scientific and Innovative Research (AcSIR), Ghaziabad, Uttar Pradesh, India.
Abstract
Smokeless tobacco (SLT) consumption is a potential health threat around the globe, predominantly in South Asian Countries. SLT products contain several carcinogens, most notably including tobacco-specific nitrosamines (TSNAs). Aryl hydrocarbon receptor (AhR), significantly higher in oral squamous cell carcinoma, is responsible for the recognition of toxic compounds and their elimination by increasing the expression of Cytochrome-P450 enzymes. However, the impact of TSNAs on AhR and AhR-related pathways remains unclear. In this work, we investigate the interaction between AhR and various TSNAs present in SLT products by molecular docking and further validate the effects of aqueous extracts (STEs) of these three SLT products on oral cancer cells (CAL-27) and human embryonic kidney cells (HEK-293). TSNA molecules docked at the classical 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) binding site of AhR. The docking results revealed the comparative binding affinity of all TSNAs molecules against AhR. Accordingly, agonist TCDD and NAT showed the highest and lowest binding affinity against AhR, respectively. Furthermore, STE exposure led to an increase in cell proliferation at low doses, whereas at high doses, inhibition of proliferation was observed against both cell lines. STE treatment showed an increase in ROS production at low doses, indicating cell transformation. AhR and AhR-dependent gene (CYP1A1, CYP1B1, Arnt, and GST) expressions were elevated upon exposure to STE. Therefore, induction of the AhR signalling network by STE exposure may be pathogenetically involved in oral carcinogenesis and future research on designing an appropriate inhibitor against AhR during SLT consumption can assist in the management of oral cancer.
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BibTeX
@article{sajid2026smokeless,
title = {{Smokeless Tobacco-Associated Nitrosamines Impact on Aryl Hydrocarbon Receptor: In Silico and In Vitro Study.}},
author = {Mohammad Sajid and Ved Vrat Verma and Varun Rawat and Sonal Srivastava and Pragya Sharma and Mausumi Bharadwaj},
journal = {Journal of biochemical and molecular toxicology},
year = {2026},
month = nov,
doi = {10.1002/jbt.71173},
url = {https://europepmc.org/article/MED/42998251},
note = {CC BY},
}
RIS
TY - JOUR
TI - Smokeless Tobacco-Associated Nitrosamines Impact on Aryl Hydrocarbon Receptor: In Silico and In Vitro Study.
AU - Mohammad Sajid
AU - Ved Vrat Verma
AU - Varun Rawat
AU - Sonal Srivastava
AU - Pragya Sharma
AU - Mausumi Bharadwaj
PY - 2026
DA - 2026/11/01
JO - Journal of biochemical and molecular toxicology
DO - 10.1002/jbt.71173
UR - https://europepmc.org/article/MED/42998251
AB - Smokeless tobacco (SLT) consumption is a potential health threat around the globe, predominantly in South Asian Countries. SLT products contain several carcinogens, most notably including tobacco-specific nitrosamines (TSNAs). Aryl hydrocarbon receptor (AhR), significantly higher in oral squamous cell carcinoma, is responsible for the recognition of toxic compounds and their elimination by increasing the expression of Cytochrome-P450 enzymes. However, the impact of TSNAs on AhR and AhR-related pathways remains unclear. In this work, we investigate the interaction between AhR and various TSNAs present in SLT products by molecular docking and further validate the effects of aqueous extracts (STEs) of these three SLT products on oral cancer cells (CAL-27) and human embryonic kidney cells (HEK-293). TSNA molecules docked at the classical 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) binding site of AhR. The docking results revealed the comparative binding affinity of all TSNAs molecules against AhR. Accordingly, agonist TCDD and NAT showed the highest and lowest binding affinity against AhR, respectively. Furthermore, STE exposure led to an increase in cell proliferation at low doses, whereas at high doses, inhibition of proliferation was observed against both cell lines. STE treatment showed an increase in ROS production at low doses, indicating cell transformation. AhR and AhR-dependent gene (CYP1A1, CYP1B1, Arnt, and GST) expressions were elevated upon exposure to STE. Therefore, induction of the AhR signalling network by STE exposure may be pathogenetically involved in oral carcinogenesis and future research on designing an appropriate inhibitor against AhR during SLT consumption can assist in the management of oral cancer.
SN - 1095-6670
SN - 1099-0461
ER -