Cytochrome P450 enzymes and oxidative stress in tobacco/nicotine mediated HIV pathogenesis
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In the US, the prevalence of cigarette smoking in the HIV-infected population is 50-70% compared to 15-20% in the general population, which further increases the risk of smoking-related health problems in this group. For example, HIV-infected smokers show decreased immune responses, poorer responses to antiretroviral therapy (ART), and greater risk of virological rebound, compared to HIV-infected non-smokers. Several in vivo and in vitro studies have shown that smoking/nicotine is associated with decreased immune responses, increased inflammation, increased oxidative stress, and increased numbers of opportunistic infections. Furthermore, in vitro studies have shown that smoking/nicotine enhances HIV replication in alveolar macrophages, microglia, and T cells. However, the mechanism by which smoking or nicotine increases HIV replication is largely unknown. As an exception, a report suggests that iron and oxidative stress are possible mechanisms of enhanced production of HIV by alveolar macrophages in cigarette smokers. The role of CYP enzymes has not been studied in context with smoking/nicotine and HIV pathogenesis. However, there are several elegant studies that show the involvement of CYP2A6, CYP2A13, CYP1A1, and CYP1B1 in smoking/nicotine-mediated toxicity leading to various types of cancers and hepatic toxicity. The majority of tobacco constituents, including nicotine, are metabolized and/or activated by CYP enzymes to generate reactive oxygen species (ROS) and/or reactive metabolites, NNK. Based on the fact that CYP pathways play a critical role in smoking mediated cell/organ toxicity, there is a critical need to explore the involvement of CYP pathways in smoking/nicotine-mediated HIV pathogenesis. The present study was based on the central hypothesis that tobacco/nicotine, or its metabolites, enhance HIV replication in monocytes/macrophages through CYP pathway. The key findings of our studies presented in this thesis indicate that (a) CYP2A6-mediated metabolism of nicotine increased the generation of ROS in HIV cell model, SVGA astrocytes, (b) Cigarette smoke condensate caused significant induction of CYP1A1, CYP2A6, ROS production, and cytotoxicity in U937 monocytes as well as enhanced HIV replication in HIV-infected primary macrophages, (c) Mild-to-moderate smoking increased viral load in HIV-infected individuals. Furthermore, our study suggested that smoking and HIV independently increase oxidative stress in the plasma as well as in monocytes. (d) There was a decrease in the level of nicotine and subsequent increase in the level of nicotine metabolites, suggesting an increase in nicotine metabolism in HIV-infected smokers compared with uninfected smokers. In conclusion, our in vitro and ex vivo results are consistent with the hypothesis that CYP and CYP-mediated oxidative stress by tobacco/nicotine are associated with increased viral load by smoking/smoking constituents. This study has clinical implications in terms of targeting CYP and oxidative stress pathways to find potentially novel therapeutic interventions, as well as drug dose adjustment to treat HIV-infected smokers effectively.
Table of Contents
Tobacco smoking mediated oxidative stress in organ toxicities: role of cytochrome P450 systems -- Tobacco smoking effect on HIV pathogenesis: role of cytochrome P450 isozymes -- General material and methods -- An LC-MS method for concurrent determination of nicotine metabolites and the role of CYP2A6 in nicotine metabolite mediated oxidative stress in SVGA astrocytes -- Cigarette smoke consensate (CSC) mediated oxidative stress and cytoxicity in U937 monocytes -- Effect of mild-tomoderate smoking on viral load, cytokines, oxidative stress, and cytochrome P450 enzymes in HIV-infected individuals -- Enhanced nicotine metabolism in HIV-positive smokers compared to HIV-negative smokers: simultaneous determination of nicotine and its four metabolites in their plasma using a simple and sensitive ESI-LC-MS/MS technique -- Summary and future directions