Bioactivation of herbal constituents: mechanisms and toxicological relevance

The increase in the application of herbal medicines and dietary products over the last decades has been accompanied with a substantial increase in case reports of herb-induced toxicities. Metabolic activation of relatively inert functional groups to chemically reactive metabolites is often considered to be an obligatory event in the etiology of drug-induced adverse reactions. Circumstantial evidence suggests that several herb-induced toxicities are a result of transformation of herbal constituents to electrophilic reactive metabolites that can covalently bind to vital macromolecules in the body, exemplified by aristolochic acids and pyrrolizidine alkaloids. At physiologically relevant concentrations, bioactivation of furanocoumarins and methylenedioxyphenyl compounds leads to mechanism-based inactivation of drug metabolizing enzymes and clinically manifested herb-drug interactions. Of particular interest is that several organic functional groups embedded in herbal constituents act as a toxicophore as well as a pharmacophore, resembling the electrophilic warheads in the development of targeted covalent inhibitors. The aim of this review is to provide a cataloging of bioactivation mechanisms of herbal substructures, structure-activity relationships, biological targets, and assist in circumventing the structural liability in the development of more effective and safer herb-based NCEs.