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

• Published in: Chemical research in toxicology 2014-09, Vol.27 (9), p.1474-1486
• Main Authors: Kandel, Sylvie E, Lampe, Jed N
• Format: Article
• Language: English
• Subjects: Animals; Cytochrome P-450 Enzyme System - chemistry; Cytochrome P-450 Enzyme System - metabolism; Cytochromes b5 - chemistry; Cytochromes b5 - metabolism; Humans; NADPH-Ferrihemoprotein Reductase - chemistry; NADPH-Ferrihemoprotein Reductase - metabolism; Pharmaceutical Preparations - metabolism; Protein Interaction Domains and Motifs; Protein Isoforms - chemistry; Protein Isoforms - metabolism; Receptors, Progesterone - chemistry; Receptors, Progesterone - metabolism; Review; Serum Albumin - chemistry; Serum Albumin - metabolism
• ISSN: 0893-228X; 1520-5010
• DOI: 10.1021/tx500203s

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.