Atypical Michaelis-Menten kinetics in cytochrome P450 enzymes: A focus on substrate inhibition

Abstract

The widespread applications of the century-old Michaelis-Menten kinetics in the characterization of drug-metabolizing cytochrome P450 enzymes have persisted since their discovery in the 1950s. This is a concern given preceding reports of atypical Michaelis-Menten kinetics in substrates and effectors of cytochrome P450 enzymes which disprove previous notions that these phenomena exist purely as experimental artifacts while highlighting the neglected risk of errors when adopting inaccurate hyperbolic kinetic models for both in vitro-in vivo extrapolation and prediction of drug-drug interactions. This commentary summarizes the various types of atypical Michaelis-Menten kinetics, such as biphasic kinetics, homotropic and heterotropic cooperativity, with a special focus on substrate inhibition kinetics, the postulated mechanisms and models in the presence and absence of a xenobiotic inhibitor and roles in regulation of endogenous metabolism. Potential artifactual sources of atypical kinetics are also discussed.

Keywords: Atypical Michaelis-Menten kinetics; Cytochrome P450 enzymes; Enzyme inhibition kinetics; In vitro-in vivo extrapolation; Substrate inhibition kinetics.