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Review
. 2019 Dec 7;20(24):6178.
doi: 10.3390/ijms20246178.

Circulating Extracellular Vesicles Containing Xenobiotic Metabolizing CYP Enzymes and Their Potential Roles in Extrahepatic Cells Via Cell-Cell Interactions

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Free PMC article
Review

Circulating Extracellular Vesicles Containing Xenobiotic Metabolizing CYP Enzymes and Their Potential Roles in Extrahepatic Cells Via Cell-Cell Interactions

Kelli Gerth et al. Int J Mol Sci. .
Free PMC article

Abstract

The cytochrome P450 (CYP) family of enzymes is known to metabolize the majority of xenobiotics. Hepatocytes, powerhouses of CYP enzymes, are where most drugs are metabolized into non-toxic metabolites. Additional tissues/cells such as gut, kidneys, lungs, blood, and brain cells express selective CYP enzymes. Extrahepatic CYP enzymes, especially in kidneys, also metabolize drugs into excretable forms. However, extrahepatic cells express a much lower level of CYPs than hepatocytes. It is possible that the liver secretes CYP enzymes, which circulate via plasma and are eventually delivered to extrahepatic cells (e.g., brain cells). CYP circulation likely occurs via extracellular vesicles (EVs), which carry important biomolecules for delivery to distant cells. Recent studies have revealed an abundance of several CYPs in plasma EVs and other cell-derived EVs, and have demonstrated the role of CYP-containing EVs in xenobiotic-induced toxicity via cell-cell interactions. Thus, it is important to study the mechanism for packaging CYP into EVs, their circulation via plasma, and their role in extrahepatic cells. Future studies could help to find novel EV biomarkers and help to utilize EVs in novel interventions via CYP-containing EV drug delivery. This review mainly covers the abundance of CYPs in plasma EVs and EVs derived from CYP-expressing cells, as well as the potential role of EV CYPs in cell-cell communication and their application with respect to novel biomarkers and therapeutic interventions.

Keywords: circulatory CYPs; cytochrome P450; exosomes; extracellular vesicles; extrahepatic tissues; plasma.

Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
Cytochrome P450 (CYP)-containing plasma extracellular vesicles (EVs)/exosomes are secreted from the liver and other peripheral organs, circulate via plasma, and are delivered to distant sites (e.g., brain cells), where they may aid in extrahepatic drug metabolism, detoxification, and may also influence toxicity at these sites. Similarly, secretion of EVs from extrahepatic cells, including brain cells are also likely to contain CYPs in addition to other biomolecules, which would also be circulated via plasma and delivered to other distant cells.
Figure 2
Figure 2
Potential applications of extracellular vesicles containing CYP enzymes include drug metabolism, prodrug activation, supplementation of CYP to subjects with genetic polymorphisms, and industrial synthesis of biomolecules.

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