Flavonoids and alkenylbenzenes: New concepts in bioactivation studies

The present paper focuses on the biological reactive intermediates formed from two categories of botanical ingredients: flavonoids and alkenylbenzenes. The paper especially presents an overview of three concepts in bioactivation studies on flavonoids and alkenylbenzenes elucidated by our recent studies. These new concepts include (i) the fact that reactive electrophilic quinone/quinone methide type metabolites of flavonoids may be the intermediates required for the induction of the beneficial gene expression through electrophile responsive element (EpRE)-mediated pathways, pointing at a possible beneficial effect of a reactive intermediate, (ii) the development of physiologically based kinetic (PBK) and physiologically based dynamic (PBD) models providing a new way to obtain insight in levels of formation of biologically reactive and unstable intermediates in vivo at high but also more realistic low dose levels, and (iii) the concept of the matrix effect that should be taken into account when studying the bioactivation of food-borne genotoxic carcinogens including the alkenylbenzenes, the bioactivation of which was shown to be inhibited by flavonoids. Together the results presented reveal that by studying the mode of action (MOA) new concepts in bioactivation studies of importance for future risk assessment and/or risk-benefit assessment of the flavonoids and alkenylbenzenes are obtained.