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.
Highlights
The cytochrome P450 (CYP) superfamily is a group of Phase I mono-oxidase enzymes with broad substrate specificity that is responsible for the majority of xenobiotic metabolism [1]
As drug metabolic capacity is limited in extrahepatic tissues, it is possible that CYP-containing plasma extracellular vesicles (EVs) are secreted from the liver, circulate via plasma, and are delivered to distant sites, where they may aid in extrahepatic drug metabolism, detoxification, and may influence toxicity at these sites (Figure 1)
CYP2A6 induction has been observed in monocytes derived from the plasma of smokers [50], and 2A6-mediated metabolism of nicotine is associated with increased oxidative stress and DNA damage in monocytic cells [13,50]
Summary
The cytochrome P450 (CYP) superfamily is a group of Phase I mono-oxidase enzymes with broad substrate specificity that is responsible for the majority of xenobiotic metabolism [1]. Hepatocytes express an abundance of drug metabolizing CYP enzymes and demonstrate the greatest capacity for Phase I xenobiotic biotransformation, followed by the small intestine and kidneys [6,7,8]. Extrahepatic CYP enzymes contribute to cell-specific biotransformation, albeit to a lesser extent than hepatic CYPs. While extrahepatic CYP expression and metabolic capacity are not able to mediate total body clearance of xenobiotics, the enzymes may play a significant role in local tissue exposure and toxicity [19]. As drug metabolic capacity is limited in extrahepatic tissues, it is possible that CYP-containing plasma EVs are secreted from the liver, circulate via plasma, and are delivered to distant sites (e.g., brain cells), where they may aid in extrahepatic drug metabolism, detoxification, and may influence toxicity at these sites (Figure 1).
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