Phytomedicine-mediated time-dependent inactivation of CYP3A4 by chemical modification

Cytochromes P450 (CYP)3A4 as the richest P450 enzyme is responsible for the metabolism of about 50% drugs. However, severe drug-drug interactions (DDIs) frequently occur when CYP3A4 is strongly inhibited by xenobiotics, which is one of the major reasons for the withdrawal of already marketed drugs. Compared to reversible inhibition, time-dependent inactivation (TDI), including mechanism-based inactivation (MBI), quasi-irreversible inactivation, and affinity-labeling inactivation, results from chemical modification of the host enzyme by electrophilic inactivators or electrophilic intermediates and is more likely to result in adverse clinical consequences. Increasing phytomedicines have been identified as time-dependent inactivators of CYP3A4 with the rapid growth of global consumption of natural products. According to vast experimental and theoretical studies, functional groups with chemical reactivity existing in phytomedicines are mainly involved in TDI of CYP3A4. For better understanding of the structure-activity relationship between phytomedicine and CYP3A4, we systematically summarize chemical mechanisms of TDI, including furan, thiophene, acetylenes, and methylenedioxyphenyl (MDP)-containing phytomedicine-induced MBI, MDP, alkylamine, and hydrazine-containing phytomedicine-induced quasi-irreversible inactivation, and iminium-containing phytomedicine-induced affinity-labeling inactivation, and comprehensively classify known natural CYP3A4 time-dependent inactivators, including polyphenols, alkaloids, terpenoids, and coumarins, which will offer the guidance and evidence for rational drug combinations and avoiding TDI-based DDIs in clinics. • Time-dependent inactivation (TDI) of cytochromes P450 (CYP)3A4 mainly includes mechanism-based inactivation, quasi-irreversible inactivation, and affinity-labeling inactivation. • Increasing phytomedicines have been identified as time-dependent inactivators of CYP3A4. • Phytomedicine-mediated TDI of CYP3A4 results from chemical modification of electrophilic inactivators or electrophilic intermediates to the host enzyme. • Methylenedioxyphenyl- and furan-containing phytomedicines account for the highest proportion of natural time-dependent inactivators of CYP3A4.