کد مقاله | کد نشریه | سال انتشار | مقاله انگلیسی | نسخه تمام متن |
---|---|---|---|---|
9017721 | 1128665 | 2005 | 7 صفحه PDF | دانلود رایگان |
عنوان انگلیسی مقاله ISI
Oxidative stress mediated toxicity exerted by ethanol-inducible CYP2E1
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کلمات کلیدی
HSCMMPCYP2E1NTABSOGCLGSHCCl4ROS - ROSArachidonic acid - اسید آراشیدونیکPolyunsaturated fatty acid - اسید چرب غیر اشباعPUFA - اسید چرب چند غیراشباعOxidative stress - تنش اکسیداتیوHepatic stellate cells - سلولهای ستارهای کبدیCytotoxicity - سمیت سلولیcytochrome P4502E1 - سیتوکروم P4502E1Glutamate–cysteine ligase - لیگاز Glutamate-CysteineNitrilotriacetate - نیترولیتریاکتاتMitochondrial membrane potential - پتانسیل غشای میتوکندریAntioxidant genes - ژنهای آنتی اکسیدانCarbon tetrachloride - کربن تتراکلریدGlutathione - گلوتاتیونReactive oxygen species - گونههای فعال اکسیژن
موضوعات مرتبط
علوم زیستی و بیوفناوری
علوم محیط زیست
بهداشت، سم شناسی و جهش زایی
پیش نمایش صفحه اول مقاله
چکیده انگلیسی
Induction of CYP2E1 by ethanol is one of the central pathways by which ethanol generates a state of oxidative stress in hepatocytes. To study the biochemical and toxicological actions of CYP2E1, our laboratory established HepG2 cell lines which constitutively overexpress CYP2E1 and characterized these cells with respect to ethanol toxicity. Addition of ethanol or an unsaturated fatty acid such as arachidonic acid or iron was toxic to the CYP2E1-expressing cells but not control cells. This toxicity was associated with elevated lipid peroxidation and could be prevented by antioxidants and inhibitors of CYP2E1. Apoptosis occurred in the CYP2E1-expressing cells exposed to ethanol, arachidonic acid, or iron. Removal of GSH caused a loss of viability in the CYP2E1-expressing cells even in the absence of added toxin or pro-oxidant. This was associated with mitochondrial damage and decreased mitochondrial membrane potential. Low concentrations of iron and arachidonic acid synergistically interacted with CYP2E1 to produce cell toxicity, suggesting these nutrients may act as priming or sensitizing agents to alcohol-induced liver injury. Surprisingly, CYP2E1-expressing cells had elevated GSH levels, due to transcriptional activation of glutamate cysteine ligase. Similarly, levels of catalase, alpha-, and microsomal glutathione transferase were also increased, suggesting that upregulation of these antioxidant genes may reflect an adaptive mechanism to remove CYP2E1-derived oxidants. Using co-cultures, interaction between CYP2E1-derived diffusible mediators to activate collagen production in hepatic stellate cells was found. While it is likely that several mechanisms contribute to alcohol-induced liver injury, the linkage between CYP2E1-dependent oxidative stress, mitochondrial injury, stellate cell activation, and GSH homeostasis may contribute to the toxic action of ethanol on the liver. HepG2 cell lines overexpressing CYP2E1 may be a valuable model to characterize the biochemical and toxicological properties of CYP2E1.
ناشر
Database: Elsevier - ScienceDirect (ساینس دایرکت)
Journal: Toxicology and Applied Pharmacology - Volume 207, Issue 2, Supplement, 1 September 2005, Pages 70-76
Journal: Toxicology and Applied Pharmacology - Volume 207, Issue 2, Supplement, 1 September 2005, Pages 70-76
نویسندگان
Defeng Wu, Arthur I. Cederbaum,