Alkaloids and nitrosamines in betel quid: A biochemical exploration of carcinogenicity

Betel quid contains two major ingredients; Areca catechu and Piper betel, often consumed with slaked lime, tobacco, certain flavouring agents, colouring agents, herbs, and spices according to personal preferences. The areca nut alkaloids (arecoline, arecaidine, guvacine, and guvacoline), and tobacco alkaloids (nicotine, nornicotine) undergo nitrosation during chewing in the oral cavity with the presence of nitrite and thiocyanate and endogenously. Among the nitrosation products generated areca nut-derived nitrosamine (ADNA): 3-(methylnitrosamino) Propionitrile (MNPN) and the two tobacco-specific nitrosamines (TSNAs); N'-nitrosonornicotine (NNN) and 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone) (NNK) are considered Group 1 human carcinogens. The slaked lime increases pH, reactive oxygen species (ROS) generation, and inflammation further lead to oral potentially malignant disorders (OPMD). The juice swallowed results in carcinogenicity, mutagenicity, and toxicity in the gastrointestinal tract including hepatocytic carcinoma, stomach, and colon cancer. Areca nut pre-treatments (sun drying, roasting, boiling, and fermentation) increase the quid metabolism, and reduce the arecoline content and associated risks. We review biochemical carcinogenesis of betel quid ingredients and synergic adverse effects and possible mechanism of carcinogenesis of betel quid in the oral cavity and gastrointestinal tract to understand the implication of polyphenols and alkaloids of areca nut and betel quid on carcinogenic nitrosamine formation under oral, gastric, and intestinal conditions.