Genetic and epigenetic instability induced by betel quid associated chemicals

Abstract

Over the years, betel quid chewing and tobacco use have attracted considerable interest as they are implicated as the most likely causative risk factors of oral and esophageal cancers. Although areca nut use and betel quid chewing may lead to apoptosis, chronic exposure to areca nut and slaked lime may promote pre-malignant and malignant transformation of oral cells. The putative mutagenic and carcinogenic mechanisms may involve endogenous nitrosation of areca and tobacco alkaloids as well as the presence of direct alkylating agents in betel quid and smokeless tobacco. Metabolic activation of carcinogenic N-nitrosamines by phase-I enzymes is required not only to elicit the genotoxicity via the reactive intermediates but also to potentiate the mutagenicity with the sporadic alkylations of nucleotide bases, resulting in the formation of diverse DNA adducts. Persistent DNA adducts provides the impetus for genetic and epigenetic lesions. The genetic and epigenetic factors cumulatively influence the development and progression of disorders such as cancer. Accumulation of numerous genetic and epigenetic aberrations due to long-term betel quid (with or without tobacco) chewing and tobacco use culminates into the development of head and neck cancers. We review recent evidence that supports putative mechanisms for mutagenicity and carcinogenicity of betel quid chewing along with tobacco (smoking and smokeless) use. The detailed molecular mechanisms of the extent of accumulation and patterns of genetic alterations, indicative of the prior exposure to carcinogens and alkylating agents because of BQ chewing and tobacco use, have not yet been elucidated.

Keywords: Alkaloids; Areca nut; DNA adducts; Epigenetic modifications; N-nitrosamines; Tobacco.

Graphical abstract

Fig. 1

Overview of carcinogenic and genotoxic attributes of BQ chewing. Addictive lifestyle habits such as AN and BQ chewing (with or without tobacco) concurrently with smoking causes long-term oral exposure to alkaloids, nitrate, carcinogens (heavy elements, PAHs, N-nitrosamines) and alkylating agents. Oral microbial flora converts nitrate to nitrite. Nitrite in oral cavity is subsequently transformed to nitrosating species in mouth and stomach (stomach tissue in inflammation also releases inducible nitric oxide, a potential nitrosating species). The ensuing encounter between nitrosating species and alkaloids in oral cavity and stomach favorably enhances the endogenous formation of carcinogenic N-nitrosamines. In addition to the metabolic activation of N-nitrosamines, exposure to carcinogens and direct alkylating agents in situ induces sporadic genetic and epigenetic aberrations.

Fig. 2

Induction of genetic and epigenetic instability due to betel quid chewing. Genetic instability includes formation of DNA adducts leading to deleterious DNA damage and promotion of chromosomal breakage. Besides, DNA mutations such as formation of novel SNP (Single Nucleotide Polymorphism), insertion-deletion mutation as well as the generation of aneuploid cells is also evident. Alterations in cell cycle pathways due to mutations and epigenetic modifications of certain cell cycle regulator genes can be observed. Epigenetic instability includes histone acetylation, methylation and promoter methylation of key regulatory genes involved in tumor suppressor defense, i.e., normal cell cycle regulation. Promotor DNA hypermethylations of tumor suppressor genes leads to the upregulation of COX-2 via NFκβ pathway. Concomitant prostaglandins production reflects the inflammation and mucosal damage, which may eventually promote the development of oral, esophageal or gastric cancer.