Microsomal monooxygenase as a multienzyme system: the role of P450-P450 interactions.

INTRODUCTION: There is increasing evidence of physical interactions (association) among cytochromes P450 in the membranes of the endoplasmic reticulum. Functional consequences of these interactions are often underestimated. AREAS COVERED: This article provides a comprehensive overview of available experimental material regarding P450-P450 interactions. Special emphasis is given to the interactions between different P450 species and to the functional consequences of homo- and heterooligomerization. EXPERT OPINION: Recent advances provide conclusive evidence for a substantial degree of P450 oligomerization in membranes. Interactions between different P450 species resulting in the formation of mixed oligomers with altered activity and substrate specificity have been demonstrated clearly. There are important indications that oligomerization impedes electron flow to a fraction of the P450 population, which renders some P450 species nonfunctional. Functional consequences of P450-P450 interactions make the integrated properties of the microsomal monooxygenase remarkably different from a simple summation of the properties of the individual P450 species. This complexity compromises the predictive power of the current in vitro models of drug metabolism and warrants an urgent need for development of new model systems that consider the interactions of multiple P450 species.