Drug-induced hepatotoxicity is a major reason for withdrawal of drugs from development as well as from the market. A major problem predicting hepatotoxicity is the lack of suitable predictive in vitro system. Drug-induced hepatotoxicity is usually associated with the recruitment of immune cells to the liver accelerating an inflammatory response often initiated by activation of the Kupffer cells.
View Article and Find Full Text PDFBackground/aims: CYP2E1 metabolizes ethanol, generates reactive oxygen species, and is suggested to be important for development of alcoholic liver disease. The present study aims to evaluate the role of CYP2E1 in combination with ethanol for development of alcoholic liver disease using mice transgenic for the human CYP2E1 gene.
Methods: Changes in hepatic gene expression were monitored in controls and mice transgenic for human CYP2E1, treated with ethanol or isocaloric dextrose intragastrically for 4 weeks, and related to pathology using Affymetrix microarrays and TaqMan RealTime PCR.
To determine the temporal relationship between alcohol-induced changes in cytokines and chemokines, development of liver pathology and stimulation of hepatocyte proliferation, male Sprague-Dawley rats were intragastrically fed low carbohydrate-containing ethanol (EtOH) diets via total enteral nutrition (TEN) for up to 49 d. Induction of EtOH metabolism and appearance of steatosis preceded development of oxidative stress, inflammation, and cell death. A transitory peak of tumor necrosis factor (TNFalpha) and interferon gamma (IFN gamma) was observed at 14 d followed by reduced expression of TNFalpha, IFN gamma and another Th1 cytokine IL-12 accompanied by reduced expression of the Th1 regulators T-bet and STAT4.
View Article and Find Full Text PDFThe effects of the dietary antioxidant N-acetylcysteine (NAC) on alcoholic liver damage were examined in a total enteral nutrition (TEN) model of ethanol toxicity in which liver pathology occurs in the absence of endotoxemia. Ethanol treatment resulted in steatosis, inflammatory infiltrates, occasional foci of necrosis, and elevated ALT in the absence of increased expression of the endotoxin receptor CD 14, a marker of Kupffer cell activation by LPS. In addition, ethanol treatment induced CYP 2 E1 and increased TNFalpha and TGFbeta mRNA expression accompanied by suppressed hepatic IL-4 mRNA expression.
View Article and Find Full Text PDFCertain human hepatocarcinoma cells undergo differentiation when grown at confluence. In order to understand the basis for this differentiation, we investigated the phenotypic changes occurring during confluent growth of the human hepatoma B16A2 cell line. The global gene expression profile of B16A2 cells grown during confluence for 5 weeks was investigated using microarrays containing complementary sequences corresponding to approximately 10,000 genes, and compared with profiles of adult human liver and HepG2 cells.
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