Role of cytochrome P450 enzymes on alcohol/nicotine-mediated oxidative stress and cytotoxicity in monocytes/astrocytes: Implications for HIV-infected alcohol/tobacco users
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Alcohol abuse is known to induce liver diseases and neurodegeneration. Chronic alcohol use during medication is known to decrease drug efficacy and increase toxicity. In addition, alcohol is known to interact with other substances of abuse, such as tobacco. Cytochrome P450 2E1 (CYP2E1), which is induced by alcohol, is mainly involved in alcohol metabolism in the liver and extra-hepatic cells in chronic users. As a result of alcohol metabolism, CYP2E1 produces reactive oxygen species (ROS), which in turn inhibits acetaldehyde dehydrogenase leading to accumulation of acetaldehyde, both of which are known to damage DNA, protein, and lipids. In addition, nicotine-metabolizing enzyme CYP2A6 and a major drug-metabolizing enzyme CYP3A4 are induced by alcohol, suggesting their role in unexpected alcohol-drug-tobacco interactions. Our central hypothesis is that CYP2A6, CYP2E1, and CYP3A4 play important role in alcohol, nicotine, and antiretroviral therapeutic (ART) drug metabolism, respectively, in monocytes/macrophages and astrocytes, leading to oxidative stress-mediated toxicity and alcohol-ART interactions. Monocytes/macrophages and astrocytes are important cell types in studying HIV-1 pathogenesis and AIDS/neuroAIDS development. Our results showed that 1) CYP2A6, CYP2E1 and CYP3A4 are induced by alcohol in U937 monocytes/macrophages, while only CYP2E1 is induced by alcohol at both mRNA and protein levels in SVGA astrocytes, 2) CYP2A6 metabolizes nicotine in U937 macrophages and SVGA astrocytes, leading to increased production of ROS, 3) CYP3A4 binds nelfinavir and other protease inhibitors (PI) and is inhibited by these PIs, 4) In both U937 monocytes and SVGA astrocytes, CYP2A6 is regulated by alcohol through oxidative stress-induced PKC/MEK/Nrf2 pathway, while CYP2E1 is regulated by oxidative stress-induced PKC/JNK/SP1 pathway, 5) In human monocytes/macrophages, CYP2E1 is induced in alcoholic as well as HIV-infected individuals. In conclusions, our findings suggested that alcohol-mediated induction of CYP2A6, CYP2E1, and CYP3A4 is responsible for increased oxidative stress, increased cytotoxicity, and decreased efficacy of ART in monocytes/macrophages and astrocytes. Since alcohol abuse and co-abuse of alcohol and tobacco are 3 times higher among HIV+ patients than that of the general population, our findings have implications in HIV-1 pathogenesis, AIDS and neuroAIDS. Our subsequent findings would help optimize ART medication and help develop alternative interventions in alcohol and tobacco-consuming HIV-infected individuals.
Table of Contents
General introduction -- General materials and methods -- Evaluation of the role of ethanol on cytochrome P450 expression -- Evaluation of the role of CYP2A6, CYP2E1 and CYP3A4 in monocytes/macrophages and astrocytes -- Mechanistic study of ethanol-mediated CYP2A6 expression: PKC-MEK-NRF2 pathway -- Mechanistic study of ethanol-induced CYP2E1 expression: PKC/JNK/SP1 pathway -- Effect of alcohol consumption on expressions of CYP2E1 and ALDH in humans -- General discussion -- Appendix