A Review on Role of Arecoline and Its Metabolites in the Molecular Pathogenesis of Oral Lesions with an Insight into Current Status of Its Metabolomics.

Aparajita Das,Sarbani Giri

doi:10.14712/23362936.2020.19

Abstract

Areca nut consumption is a popular habit in Southeast Asian countries. One of the important biologically active alkaloids of areca nut is arecoline, which plays a role in mediating the development of several pathologies of the primary exposure site, the oral cavity. Studies on the metabolism of arecoline revealed the formation of several metabolites which themselves might be toxic. Moreover, polymorphisms in genes encoding enzymes involved in the metabolism of arecoline might predispose an organism towards the development of oral cancer. The present review tries to accumulate all the relevant existing literature and then elucidate the molecular mechanism by which arecoline plays a role in the development of oral submucous fibrosis and oral cancer. Existing information regarding arecoline metabolism, enzymes involved in the metabolic process and biological effects of the metabolites of arecoline have also been compiled and compared to study the toxicity of metabolites with its parent compound arecoline and whether they play any role in the pathogenesis of oral cancer mediated by areca nut consumption. A repertoire of molecular targets has come up in the discussion whose expression profile is perturbed by arecoline. Construction of induction cascade from existing literature has given an idea about the process of molecular pathogenesis. The summarized and analysed data can help to determine the molecular mechanism and drug targets, which in turn could be helpful in the prevention or treatment of these pathological conditions. It also brings into light areas where further research needs to be directed.

Highlights

Mortality is a severe issue in the case of oral cancer, as indicated by the International Agency for Research in Cancer (IARC) report, GLOBOCAN series, 2012
NGL and MNPN were detected in the saliva of betel quid chewers in the range of 2.2–9.5 μg/l and 0.5–11.4 μg/l, respectively (Wenke et al, 1984a; Prokopczyk et al, 1987). These findings indicate that nitrosation of arecoline does take place in the oral cavity of areca nut consumers, and thereby, buccal cells do get exposed to these nitrosated metabolites on chewing areca nut
Mitochondrial metabolism of arecoline N-oxide by the above-mentioned enzymes might be responsible for the generation of reactive oxygen species (ROS), which mediates the toxic effects of the compound

Summary

Introduction

Mortality is a severe issue in the case of oral cancer, as indicated by the International Agency for Research in Cancer (IARC) report, GLOBOCAN series, 2012. Expression profiles of several extracellular matrix (ECM) proteins, enzymes, growth factors, and transcription factors are altered under the effect of arecoline (Figure 3) All these factors work in an association as indicated by several studies involving fibroblasts, epithelial cells and cancer cell lines (Tables 1 and 2). Advanced/advanced OSF specimen showed higher expression of hypoxia inducible factor-1α in fibroblasts, epithelial cells and inflammatory cells. After exposure of cells from cancer cell line to arecoline for an extended period of time, increased expression of metalloproteinases MMP-8 and MMP-1 was observed (Liu et al, 2007; Lee et al, 2008) This might indicate that under already initiated and promoted tumour conditions, arecoline might play a role in the progression of areca nut induced carcinogenesis. Induced tumour in several organ of exposed rats (Nishikawa et al, 1992)

18. N-nitrosonipecotic acid

Conclusion