| The special size and structure give nanomaterials superior optical, electrical, thermal and mechanical properties, which have aroused tremendous interesting. Carbon nanotubes are seamless cylinders with unique surface molecular structure, which have been studied for application in many fields, especially in biomedicine. Moreover, the huge specific surface area and hollow structure makes carbon nanotube capable for various modification, which can improve their solubility, biocompatibility or even targeting. The different modification can thus expand the application of CNTs in biomedical and disease treatment. Research have found that CNTs can interact strongly with proteins, by means of electronstatic interaction, hydrophobic effects, and π-π stacking. These interactions could change the conformation of proteins, thus disturb their normal physiological function. As the increasing application of CNTs, it is inevitable that they will get into body. Studies have found that CNTs could accumulate in liver, spleen, lung easily after exposed to animal. Cytochromes P450(CYP) are the most important enzymes in human body, which catalyze the metabolic of most endogenous and exogenous compounds. Research showed that many factors could lead to induction or inhibition of CYP enzymes, which may bring ignored influence to body. Therefore, it is necessary to study the influence of CNTs on CYP activity.Our research based on a f-MWCNTs library including80kinds of different surface modified MWCNTs, and studied the regulation of different surface chemistry on the metabolic activity of CYP3A4. We incubate human liver microsome (HLM) in vitro as a model to imitate the in vivo drug metabolic reaction, the surplus drug can be used to reflect the activity of CYP3A4, and nifedipine is used as probe substrate of CYP3A4. In order to explore the mechanism of different effects on nifedipine pharmacokinetics, we put forward three different reaction models for the first time. We found that different surface chemistry can regulate the metabolic activity of CYP3A4, but the influence on nifedipine pharmoacokinetics is the result of interaction among CNTs, CYP3A4and nifedipine. Different changes happened to the metabolism of nifedipine when changed the reaction order, and the effects were not due to the ligands or MWCNT themselves.In order to further assess the influence of f-MWCNTs on CYP3A4in vivo, we choose31#and84#f-MWCNTs to study the metabolic activity of CYP3A4in mice. After exposed to f-MWCNTs intravenously, the pharmacokinetics of nifedipine in ICR mice were studied. The change of nifedipine metabolic reveals the variation of CYP3A4activity. We found that at the low dose of CNTs in our study, there were no apparent change for the pharmacokinetics of nifedipine compared with the result of negative control. After observed the liver slices, we found that f-MWCNTs were almost engulfed by Kuffer cells in liver, and no f-MWCNTs have been found in hepatocytes. We supposed that because of the macrophage, f-MWCNTs have no chance to meet CYP3A4in liver, thus have no influence on paharmacokinetics of nifedipine.In summary, we found that different surface functionalization of MWCNTs can regulate the metabolic activity of CYP3A4in vitro, while the pharmacokinetics of drug can be disturbed by absorption of both CYP3A4and nifedipine on f-MWCNTs. In mice, low dose of f-MWCNTs have little influence on CYP3A4activity. We establish the model for evaluating the effects of f-MWCNTs on metabolic enzymes in vitro and in vivo, and give strong supporting for accessment of CNTs toxicity and its application in nanomedicine. |
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