Nicotine self-administration with menthol and audiovisual cue facilitates differential packaging of CYP2A6 and cytokines/chemokines in rat plasma extracellular vesicles

Asit Kumar,Angel G Martinez,Namita Sinha,Santosh Kumar,Sunitha Kodidela,Tengfei Wang,Sanjana Haque,Hao Chen

doi:10.1038/s41598-021-96807-5

Asit Kumar, Angel G Martinez + Show 6 more

Open Access

https://doi.org/10.1038/s41598-021-96807-5

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Abstract

In this study, we investigated whether intravenously self-administered nicotine with menthol and audiovisual cue modulates nicotine-metabolizing CYP2A6, oxidative stress modulators, and cytokines/chemokines in plasma extracellular vesicles (EVs) in rats. We assigned rats to self-administered nicotine with: (a) audiovisual cue (AV), (b) menthol, and (c) menthol and AV cue. We found increased levels of CD9 in plasma EVs after self-administered nicotine with menthol and AV cue. Moreover, expression of CYP2A6 in plasma EVs was significantly increased after self-administered nicotine in response to menthol and AV cue. However, despite an upward trend on SOD1 and catalase, increase was not found to be statistically significant, while total antioxidant capacity was found to be significantly increased in plasma and plasma EVs obtained after self-administered nicotine with menthol and AV cue. Among cytokine and chemokine profiling, we found a significant increase in the levels of MCP-1 after self-administered nicotine with menthol and AV cue and complete packaging of IL-1β in EVs. Taken together, the study provides evidence that nicotine in response to menthol and AV cues can package altered levels of CYP2A6, and cytokines/chemokines in plasma EVs that may contribute to cell–cell communication, nicotine metabolism, and inflammation upon cigarette smoking.

Highlights

Cytochrome P450 2A6 (CYP2A6) is known to metabolize nicotine, the major constituent of tobacco, leading to the production of toxic metabolites and induction of oxidative stress that result in tissue damage and disease progression such as liver damage and lung cancer, r espectively[1]
The level of these proteins appear to increase after nicotine self-administration, which is consistent with an increased levels of total proteins (Fig. 1b vs. a)
We confirmed the quality of extracellular vesicles (EVs) by measuring their size distribution, which is in the range of 100–150 nm and acetylcholine esterase (AChE) activity

Summary

Introduction

Cytochrome P450 2A6 (CYP2A6) is known to metabolize nicotine, the major constituent of tobacco, leading to the production of toxic metabolites and induction of oxidative stress that result in tissue damage and disease progression such as liver damage and lung cancer, r espectively[1]. We have shown that CYP2A6 is induced by ethanol and metabolizes nicotine into cotinine and other metabolites leading to a generation of ROS in U937 monocytes[13] These extrahepatic cells express a much lower (< tenfold) amount of CYP enzymes including CYP2A6 compared to liver[14]. CYP2A6 as well as other modulators of oxidative stress such as antioxidant enzymes (AOEs) and inflammatory cytokines and chemokines may be circulated via plasma and taken up by extrahepatic cells The translocation of these modulators may occur via extracellular vesicles (EVs) or exosomes, which are released from most tissues and organs and package a variety of biomolecules[15]. Since an audiovisual (AV) has been found to facilitate nicotine intake[6], we studied the interaction between nicotine, menthol, and an AV cue in this study

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