Genetic toxicology and toxicokinetics of arecoline and related areca nut compounds: an updated review

Areca nut (AN) is consumed by more than 600 million of individuals, particularly in some regions of South Asia, East Africa, and tropical Pacific, being classified as carcinogenic to humans. The most popular way of exposure consists of chewing a mixture of AN with betel leaf, slaked lime, and other ingredients that may also contain tobacco named betel quid (BQ). Arecoline is the principal active compound of AN, and, therefore, has been systematically studied over the years in several in vitro and in vivo genotoxicity endpoints. However, much of this information is dispersed, justifying the interest of an updated and comprehensive review article on this topic. In this sense, it is thus pertinent to describe and integrate the genetic toxicology data available as well as to address key toxicokinetics aspects of arecoline. This review also provides information on the effects induced by arecoline metabolites and related compounds, including other major AN alkaloids and nitrosation derivatives. The complexity of the chemicals involved renders this issue a challenge in genetic toxicology. Overall, positive results in several endpoints have been reported, some of them suggesting a key role for arecoline metabolites. Nevertheless, some negative genotoxicity findings for this alkaloid in short-term assays have also been reported in the literature. Finally, this article also collates information on the potential mechanisms of arecoline-induced genotoxicity, and suggests further approaches to tackle this important toxicological issue.

Automated summary

Areca nut is consumed by over 600 million individuals and classified as carcinogenic to humans, particularly in South Asia, East Africa, and tropical Pacific regions. Arecoline is the principal active compound of Areca nut and has been systematically studied in several in vitro and in vivo genotoxicity endpoints. The complexity of the chemicals involved in Areca nut makes it a challenge in genetic toxicology, with both positive and negative genotoxicity findings reported in the literature.