The functional effects of physical interactions involving cytochromes P450: putative mechanisms of action and the extent of these effects in biological membranes

Abstract

Cytochromes P450 represent a family of enzymes, which are responsible for the oxidative metabolism of a wide variety of xenobiotics. Although the mammalian P450s require interactions with their redox partners in order to function, more recently, P450 system proteins have been shown to exist as multi-protein complexes that include the formation of P450•P450 complexes. Evidence has shown that the metabolism of some substrates by a given P450 can be influenced by the specific interaction of the enzyme with other forms of P450. Detailed kinetic analysis of these reactions in vitro has shown that the P450–P450 interactions can alter metabolism by changing the ability of a P450 to bind to its cognate redox partner, NADPH-cytochrome P450 reductase; by altering substrate binding to the affected P450; and/or by changing the rate of a catalytic step of the reaction cycle. This review summarizes the known examples of P450–P450 interactions that have been shown in vitro to influence metabolism and categorizes them according to the mechanism(s) causing the effects. P450–P450 interactions have the potential to cause major changes in the metabolism and elimination of drugs in vivo. This review summarizes the evidence that the P450–P450 interactions influence metabolism in biological membranes and discusses the studies, which will provide further insight into the extent of these effects in the future.

Keywords:

• Cytochrome P450
• protein–protein interactions
• drug metabolism
• enzyme inhibition
• enzyme activation

Disclosure statement

The authors report no conflicts of interest. The authors alone are responsible for the content and writing of this article.

Funding

This work was supported by US Public Health Service Research Grants from the National Institute of Environmental Health Sciences [ES013648 to WLB, JRR and ES004344 to WLB].