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

Dmitri R Davydov1

  • 1University of California - San Diego, Skaggs School of Pharmacy and Pharmaceutical Sciences, La Jolla, CA 92093, USA. ddavydov@ucsd.edu

Expert Opinion on Drug Metabolism & Toxicology
|March 15, 2011
PubMed
Abstract

Insights

Cytochromes P450 (CYPs) associate in endoplasmic reticulum membranes, forming oligomers. These interactions alter enzyme activity and drug metabolism, necessitating new predictive models.

Area of Science:

  • Biochemistry
  • Molecular Biology
  • Cellular Biology

Background:

  • Increasing evidence suggests physical interactions (association) among cytochromes P450 (CYPs) within endoplasmic reticulum membranes.
  • The functional consequences of these CYP-CYP interactions are frequently underestimated in current research.

Purpose of the Study:

  • To provide a comprehensive overview of experimental data on P450-P450 interactions.
  • To emphasize interactions between different P450 species and their functional outcomes.
  • To explore the consequences of homo- and heterooligomerization on enzyme function.

Main Methods:

  • Literature review of experimental studies on P450-P450 interactions.
  • Analysis of data concerning homo- and heterooligomerization of P450 enzymes.
  • Evaluation of functional consequences, including altered activity and substrate specificity.

Main Results:

  • Conclusive evidence supports significant P450 oligomerization in biological membranes.
  • Interactions between different P450 species form mixed oligomers with modified activity and substrate specificity.
  • Oligomerization can impede electron transfer, rendering a portion of the P450 population nonfunctional.

Conclusions:

  • P450-P450 interactions create complex microsomal monooxygenase properties, differing from simple additive effects.
  • Current in vitro models for drug metabolism have limited predictive power due to these interactions.
  • There is an urgent need for novel model systems that incorporate multi-P450 species interactions.

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