کد مقاله | کد نشریه | سال انتشار | مقاله انگلیسی | نسخه تمام متن |
---|---|---|---|---|
2569646 | 1128543 | 2011 | 15 صفحه PDF | دانلود رایگان |
عنوان انگلیسی مقاله ISI
The enhanced value of combining conventional and “omics” analyses in early assessment of drug-induced hepatobiliary injury
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کلمات کلیدی
TβMCAXMELOQAsparate aminotransferasecholateTCAGCAALTLC/MS - LC / MSAST - آسپارتات ترانس آمینازAlanine aminotransferase - آلانین آمینوترانسفرازALP - آلکالن فسفاتازAlkaline phosphatase - آلکالین فسفاتاز یا فسفاتاز قلیاییtaurocholate - تاوروکولاتPeroxisome proliferation - ترویج پراکسیومHigh dose - دوز بالاlow dose - دوز کمDrug-induced hepatotoxicity - سمیت کبدی ناشی از مواد مخدرToxicogenomics - سمژنگانشناسیXenobiotic metabolism - سوخت و ساز بدن XenobioticSVM - ماشین بردار پشتیبانیSupport vector machine - ماشین بردار پشتیبانیMetabolomics - متابولومیکMetabonomics - متابونومیکس Transcriptomics - متن ترانهlimit of quantification - محدودیت اندازه گیریProteomics - پروتئومیکسLiver - کبدGlycocholate - گلیکوکولات
موضوعات مرتبط
علوم زیستی و بیوفناوری
علوم محیط زیست
بهداشت، سم شناسی و جهش زایی
پیش نمایش صفحه اول مقاله
چکیده انگلیسی
The InnoMed PredTox consortium was formed to evaluate whether conventional preclinical safety assessment can be significantly enhanced by incorporation of molecular profiling (“omics”) technologies. In short-term toxicological studies in rats, transcriptomics, proteomics and metabolomics data were collected and analyzed in relation to routine clinical chemistry and histopathology. Four of the sixteen hepato- and/or nephrotoxicants given to rats for 1, 3, or 14Â days at two dose levels induced similar histopathological effects. These were characterized by bile duct necrosis and hyperplasia and/or increased bilirubin and cholestasis, in addition to hepatocyte necrosis and regeneration, hepatocyte hypertrophy, and hepatic inflammation. Combined analysis of liver transcriptomics data from these studies revealed common gene expression changes which allowed the development of a potential sequence of events on a mechanistic level in accordance with classical endpoint observations. This included genes implicated in early stress responses, regenerative processes, inflammation with inflammatory cell immigration, fibrotic processes, and cholestasis encompassing deregulation of certain membrane transporters. Furthermore, a preliminary classification analysis using transcriptomics data suggested that prediction of cholestasis may be possible based on gene expression changes seen at earlier time-points. Targeted bile acid analysis, based on LC-MS metabonomics data demonstrating increased levels of conjugated or unconjugated bile acids in response to individual compounds, did not provide earlier detection of toxicity as compared to conventional parameters, but may allow distinction of different types of hepatobiliary toxicity. Overall, liver transcriptomics data delivered mechanistic and molecular details in addition to the classical endpoint observations which were further enhanced by targeted bile acid analysis using LC/MS metabonomics.
ناشر
Database: Elsevier - ScienceDirect (ساینس دایرکت)
Journal: Toxicology and Applied Pharmacology - Volume 252, Issue 2, 15 April 2011, Pages 97-111
Journal: Toxicology and Applied Pharmacology - Volume 252, Issue 2, 15 April 2011, Pages 97-111
نویسندگان
Heidrun Ellinger-Ziegelbauer, Melanie Adler, Alexander Amberg, Arnd Brandenburg, John J. Callanan, Susan Connor, Michael Fountoulakis, Hans Gmuender, Albrecht Gruhler, Philip Hewitt, Mark Hodson, Katja A. Matheis, Diane McCarthy, Marian Raschke,