Effect of alcohol on drug efflux protein and drug metabolic enzymes in U937 macrophages.
Effect of alcohol on drug efflux protein and drug metabolic enzymes in U937 macrophages.
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DOI：
10.1111/j.1530-0277.2010.01330.x
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发表时间：
2011-01
期刊：
影响因子：
--
通讯作者：
Kumar S
中科院分区：
文献类型：
--
作者：
Jin M;Arya P;Patel K;Singh B;Silverstein PS;Bhat HK;Kumar A;Kumar S
atp结合盒（ABC）蛋白和细胞色素P450 （CYP）酶调节HIV-1抗逆转录病毒治疗（ART）药物、非核苷类逆转录酶抑制剂（NNRTIs）和蛋白酶抑制剂（pi）的生物利用度。它们还参与调节和响应包括肝脏在内的各种组织和器官的氧化应激。本研究旨在评估酒精对U937巨噬细胞中参与NNRTIs和pi代谢（CYP2B6、CYP2D6、CYP3A4）和氧化应激（CYP1A1、CYP2A6、CYP2E1）的ABCC1和CYP酶的影响。U937细胞系已被用作人巨噬细胞的体外模型。ABCC1和CYP酶在U937巨噬细胞中的表达水平通过mRNA定量、蛋白分析和功能活性测定进行表征。此外，通过测定氧化应激标记酶的活性和活性氧（ROS）的产生来监测氧化应激。U937巨噬细胞mRNA的表达顺序为ABCC1 ~ CYP2A6 > CYP3A4 ~ CYP2E1 ~ CYP1A1 > CYP2D6 > CYP2B6。与对照相比，酒精（100 mM）使ABCC1和CYP2A6 mRNA水平升高200%，使CYP2B6和CYP3A4 mRNA水平升高150%，使CYP2E1 mRNA水平升高400%。酒精导致U937巨噬细胞中ABCC1、CYP2A6、CYP2E1和CYP3A4蛋白显著上调（50-85%），CYP2A6和CYP3A4特异性活性增加约50%。此外，酒精增加了U937巨噬细胞中ROS的产生，并显著提高了氧化应激标记酶、超氧化物歧化酶和过氧化氢酶的活性。我们的研究表明，酒精导致U937巨噬细胞中ABCC1和CYP酶的遗传和功能表达增加。这项研究对酒精性HIV-1个体具有临床意义，因为据报道，饮酒会降低nnrti和PIs的治疗效果，并增加氧化应激。
ATP-binding cassette (ABC) proteins and cytochrome P450 (CYP) enzymes regulate the bioavailability of HIV-1 antiretroviral therapeutic (ART) drugs, non-nucleoside reverse transcriptase inhibitors (NNRTIs) and protease inhibitors (PIs). They are also involved in regulating, and responding to, oxidative stress in various tissues and organs including liver. The present study is designed to assess the effect of alcohol on the ABCC1 and CYP enzymes involved in the metabolism of NNRTIs and PIs (CYP2B6, CYP2D6, CYP3A4) and oxidative stress (CYP1A1, CYP2A6, CYP2E1) in U937 macrophages. The U937 cell line has been utilized as an in vitro model of human macrophages. The expression levels of the ABCC1 and CYP enzymes in U937 macrophages were characterized in terms of mRNA quantification, protein analysis, and assays for functional activity. In addition, oxidative stress was monitored by measuring the activities of oxidative stress marker enzymes and production of reactive oxygen species (ROS). The order of mRNA expression in U937 macrophages was ABCC1 ~ CYP2A6 > CYP3A4 ~ CYP2E1 ~ CYP1A1 > CYP2D6 > CYP2B6. Alcohol (100 mM) increased the mRNA levels of ABCC1 and CYP2A6 (200%), CYP2B6 and CYP3A4 (150%), and CYP2E1 (400%) compared with the control. Alcohol caused significant upregulation of ABCC1, CYP2A6, CYP2E1, and CYP3A4 proteins (50-85%) and showed >50% increase in the specific activity of CYP2A6 and CYP3A4 in U937 macrophages. Furthermore, alcohol increased the production of ROS and significantly enhanced the activity of oxidative stress marker enzymes, superoxide dismutase and catalase in U937 macrophages. Our study showed that alcohol causes increases in genetic and functional expressions of ABCC1 and CYP enzymes in U937 macrophages. This study has clinical implications in alcoholic HIV-1 individuals, because alcohol consumption is reported to reduce the therapeutic efficacy of NNRTIs and PIs and increases oxidative stress.
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影响因子：
6.4
作者：
McCartney, Erin M.;Semendric, Ljiljana;Beard, Michael R.
通讯作者：
Beard, Michael R.
影响因子：
2.9
作者：
Lee, CGL;Gottesman, MM;Dey, S
通讯作者：
Dey, S
影响因子：
4.1
作者：
Fukami, Tatsuki;Katoh, Miki;Nakajima, Miki
通讯作者：
Nakajima, Miki
DOI：
10.1073/pnas.021551798
发表时间：
2001-01-16
影响因子：
11.1
作者：
Igarashi, T;Brown, CR;Martin, MA
通讯作者：
Martin, MA
影响因子：
7.4
作者：
Haorah, James;Ramirez, Servio H.;Floreani, Nicholas;Gorantla, Santhi;Morsey, Brenda;Persidsky, Yuri
通讯作者：
Persidsky, Yuri