کد مقاله | کد نشریه | سال انتشار | مقاله انگلیسی | نسخه تمام متن |
---|---|---|---|---|
5824341 | 1118507 | 2007 | 11 صفحه PDF | دانلود رایگان |
عنوان انگلیسی مقاله ISI
Alcohol-induced S-adenosylhomocysteine accumulation in the liver sensitizes to TNF hepatotoxicity: Possible involvement of mitochondrial S-adenosylmethionine transport
دانلود مقاله + سفارش ترجمه
دانلود مقاله ISI انگلیسی
رایگان برای ایرانیان
کلمات کلیدی
SAHLPSterminal deoxynucleotidyl transferase biotin-dUTP nick end labelingTNFDZAS-adenosylhomocysteinePLPGSHSAMALD - آدرنولکودیستروفیS-adenosylmethionine - اس-ادنوزیل متیونینalcoholic liver disease - بیماری کبدی الکلیELISA - تست الیزاEnzyme-linked immunosorbent assay - تست الیزاtumor necrosis factor α - تومور نکروز عامل αTUNEL - تونلSAHH - شفاtumor necrosis factor - فاکتور نکروز تومورlipopolysaccharide - لیپوپلی ساکاریدMat - ماتMitochondria - میتوکندریاPyridoxal 5-phosphate - پرییدکسل 5-فسفاتLiver - کبدhigh performance liquid chromatography - کروماتوگرافی مایع با کارایی بالاHPLC - کروماتوگرافی مایعی کاراGlutathione - گلوتاتیون
موضوعات مرتبط
علوم پزشکی و سلامت
داروسازی، سم شناسی و علوم دارویی
داروشناسی
پیش نمایش صفحه اول مقاله
چکیده انگلیسی
Hepatocytes are resistant to tumor necrosis factor-α- (TNF) induced killing/apoptosis under normal circumstances, but primary hepatocytes from rats chronically fed alcohol have increased TNF cytotoxicity. Therefore, there must be mechanism(s) by which alcohol exposure “sensitizes” to TNF hepatotoxicity. Abnormal metabolism of methionine and S-adenosylmethionine (SAM) are well-documented acquired metabolic abnormalities in ALD. S-adenosylhomocysteine (SAH) is the product of SAM in hepatic transmethylation reactions, and SAH hydrolase (SAHH) is the only enzyme to metabolize SAH to homocysteine and adenosine. Our previous studies demonstrated that chronic intracellular accumulation of SAH sensitized hepatocytes to TNF cytotoxicity in vitro. In the current study, we extended our previous observations by further characterizing the effects of chronic alcohol intake on mitochondrial SAM levels in liver and examining its possible involvement in SAH sensitization to TNF hepatotoxicity. Chronic alcohol consumption in mice not only increased cytosolic SAH levels, but also decreased mitochondrial SAM concentration, leading to decreased mitochondrial SAM to SAH ratio. Moreover, accumulation of hepatic SAH induced by administration of 3-deaza-adenosine (DZA-a potent inhibitor of SAHH) enhanced lipopolysaccharide (LPS)/TNF hepatotoxicity in mice in vivo. Inhibition of SAHH by DZA resulted not only in accumulation of cytoplasmic SAH, but also in depletion of the mitochondrial SAM pool. Further studies using mitochondrial SAM transporter inhibitors showed that inhibition of SAM transport into mitochondria sensitized HepG2 cells to TNF cytotoxicity. In conclusion, our results demonstrate that depletion of the mitochondrial SAM pool by SAH, which is elevated during chronic alcohol consumption, plays a critical role in SAH induced sensitization to TNF hepatotoxicity.
ناشر
Database: Elsevier - ScienceDirect (ساینس دایرکت)
Journal: Biochemical Pharmacology - Volume 74, Issue 3, 1 August 2007, Pages 521-531
Journal: Biochemical Pharmacology - Volume 74, Issue 3, 1 August 2007, Pages 521-531
نویسندگان
Zhenyuan Song, Zhanxiang Zhou, Ming Song, Silvia Uriarte, Theresa Chen, Ion Deaciuc, Craig J. McClain,