Atypical kinetics of cytochrome P450 enzymes in pharmacology and toxicology.

Abstract

Atypical kinetics are observed in metabolic reactions catalyzed by cytochrome P450 enzymes (P450). Yet, this phenomenon is regarded as experimental artifacts in some instances despite increasing evidence challenging the assumptions of typical Michaelis-Menten kinetics. As P450 play a major role in the metabolism of a wide range of substrates including drugs and endogenous compounds, it becomes critical to consider the impact of atypical kinetics on the accuracy of estimated kinetic and inhibitory parameters which could affect extrapolation of pharmacological and toxicological implications. The first half of this book chapter will focus on atypical non-Michaelis-Menten kinetics (e.g. substrate inhibition, biphasic and sigmoidal kinetics) as well as proposed underlying mechanisms supported by recent insights in mechanistic enzymology. In particular, substrate inhibition kinetics in P450 as well as concurrent drug inhibition of P450 in the presence of substrate inhibition will be further discussed. Moreover, mounting evidence has revealed that despite the high degree of sequence homology between CYP3A isoforms (i.e. CYP3A4 and CYP3A5), they have the propensities to exhibit vastly different susceptibilities and potencies of mechanism-based inactivation (MBI) with a common drug inhibitor. These experimental observations pertaining to the presence of these atypical isoform- and probe substrate-specific complexities in CYP3A isoforms by several clinically-relevant drugs will therefore be expounded and elaborated upon in the second half of this book chapter.