Role of Protein–Protein Interactions in Cytochrome P450-Mediated Drug Metabolism and Toxicity

Abstract

Through their unique oxidative chemistry, cytochrome P450 monooxygenases (CYPs) catalyze the elimination of most drugs and toxins from the human body. Protein–protein interactions play a critical role in this process. Historically, the study of CYP–protein interactions has focused on their electron transfer partners and allosteric mediators, cytochrome P450 reductase and cytochrome b5. However, CYPs can bind other proteins that also affect CYP function. Some examples include the progesterone receptor membrane component 1, damage resistance protein 1, human and bovine serum albumin, and intestinal fatty acid binding protein, in addition to other CYP isoforms. Furthermore, disruption of these interactions can lead to altered paths of metabolism and the production of toxic metabolites. In this review, we summarize the available evidence for CYP protein–protein interactions from the literature and offer a discussion of the potential impact of future studies aimed at characterizing noncanonical protein–protein interactions with CYP enzymes.

Membrane Associated Progesterone Receptors: Promiscuous Proteins with Pleiotropic Functions – Focus on Interactions with Cytochromes P450

“…This “dark variation” may be explained by so far unidentified or unexplored genes that influence drug metabolism at the level of protein-protein interactions (PPI). The multiple monooxygenase functions of microsomal CYP enzymes strictly depend on PPI with the single microsomal flavoprotein NADPH:cytochrome P450 oxidoreductase (POR) to allow electron transfer from NADPH to the heme iron (Pandey and Fluck, 2013; Kandel and Lampe, 2014). Since POR is present in the endoplasmic reticulum (ER) at sub-stoichiometric amounts compared to CYP, it has been proposed that their interactions involve transient oligomeric complexes (Backes and Kelley, 2003).…”

Photo-initiated crosslinking extends mapping of the protein–protein interface to membrane-embedded portions of cytochromes P450 2B4 and b5

“…Except 2:1 cytochrome b 5 :P450 complex also 1:2 cytochrome b 5 :P450 complex was detected. Because such a multimeric complexes of P450-P450 are not considered to be non-physiological [31] and cytochrome b 5 may also serve P450 as an alternative source of electron or an "electron shuttle" [38], the close P450-redox partner contact and their heterooligomerization should not be also omitted [39].…”

Integrative network analysis of rifampin-regulated miRNAs and their functions in human hepatocytes

“…The rifampin-associated miRNAs and genes are listed in Table 3. A total of 33 different rifampin-associated genes were identified (Table 3). Among them, P450 and CYP3A5 have been reported to have important roles in drug metabolism [28][29][30], and SP3, ARF6, CEBPA, RELA are responsible for liver development [31][32][33][34]. In addition, CXCL13 and RELA have been previously reported as inflammatory markers [35,36].…”