Mechanism-based inactivation of cytochrome P450 enzymes by natural products based on metabolic activation

Abstract

Cytochrome P450 enzymes (P450 enzymes) are the most common and important phase I metabolic enzymes and are responsible for the majority of the metabolism of clinical drugs and other xenobiotics. Drug-drug interactions (DDIs) can occur when the activities of P450 enzymes are inhibited. In particular, irreversible inhibition of P450 enzymes may lead to severe adverse interactions, compared to reversible inhibition. Many natural products have been shown to be irreversible inhibitors of P450 enzymes. The risks for intake of naturally occurring irreversible P450 enzyme inhibitors have been rising due to the rapid growth of the global consumption of natural products. Irreversible inhibition is usually called mechanism-based inactivation, which is time-, concentration- and NADPH- dependent. Generally, the formation of electrophilic intermediates is fundamental for the inactivation of P450 enzymes. This review comprehensively classifies natural P450 enzyme inactivators, including terpenoids, phenylpropanoids, flavonoids, alkaloids, and quinones obtained from herbs or foods. Moreover, the structure − activity correlations according to the IC₅₀ (or K_i) values reported in the literature as well as the underlying mechanisms based on metabolic activation are highlighted in depth.

Keywords:

• natural products
• P450 enzymes
• mechanism-based inactivation
• metabolic activation
• DDI
• covalent binding

Disclosure statement

No potential conflict of interest was reported by the author(s).

Additional information

Funding

This work was supported by the Technology Major Project of China ‘Key New Drug Creation and Manufacturing Program’ [2017ZX09301012-001], the National Nature Science Foundation of China [Grant No. 81803615]), and the Program of 131 Talents of Tianjin [YL2001020242].