Oral cancer incidence is alarmingly increasing in the Southeast Asian population due to increased usage of smoke, smokeless tobacco and alcohol products that account for 11.8% of cancer incidence in India . In addition to that, tobacco chewing and smoking also cause lung, esophagus, liver, kidney, bladder, cervical cancers and cardiovascular diseases . As per the WHO report, tobacco has more than 4000 chemicals, and more than 50 compounds are classified as carcinogens . The metabolism of these exogenous compounds undergoes through Phase I and Phase II detoxification systems. In phase I, the oxygenation of xenobiotics into water-soluble compounds is taken care of by the CYP450 Heme binding enzymes, which are followed by phase II enzymes .
Cytochrome P450 is a member of the CYP gene family, localized at 15q24.1, and codes for aryl hydrocarbon hydroxylase (AHH) [5, 6]. The expression of the CYP1A1 enzyme alters the xenobiotics’ metabolism and may increase the risk of cancer development . CYP1A1 metabolizes exogenous xenobiotics and endogenous substrates too. It metabolizes the tobacco components, particularly carcinogenic polycyclic aromatic hydrocarbons (PAH) to phenol and epoxide which forms DNA adducts a mutagenic event. CYP1A1 expression can be modulated by aryl hydrocarbon receptor, a PAH inducible transcription factor .
Single nucleotide polymorphism (SNPs) in the gene coding region, generally considered as a genetic variation associated with several human diseases. In addition to mutation, polymorphisms in the CYP1A1 gene can alter its expression and function [9, 10]. Two important notable variations found in oral cancer are threonine/asparagine substitution at 461 positions and isoleucine/valine or phenylalanine substitution at 462 positions of the CYP1A1 gene, results in increased activity of the enzyme as well as activation of procarcinogen and mutagenic activity [11, 12]. Several algorithm-based tools and online servers are currently available for determining the impact of the selected variants of the CYP1A1 gene and their interaction with the carcinogenic metabolite(s) of tobacco. We employed Desmond software for molecular dynamic simulation methods to get insight into the atomic-level alterations and dynamic behaviour of the CYP1A1 on the specific mutation location. In the literature study, we observe that the wild and our study identified variants in CYP1A1 (T461N, I462V, and I462F) structural and functional behavior change, concerning we did molecular simulation studies and conform the RMSD and RMSF of C-α atoms of CYP1A1. It was noted that the variant has shown more fluctuations compared to wild-type CYP1A1 except I462V. The present in silico study is useful for categorizing precise variants in the CYP1A1 gene particularly before attempting in vitro studies to find the definite gene regions which may have possible functional variation due to polymorphism.