DRUG AND ALCOHOL INDUCED HEPATOTOXICITY

摘要: Drug induced hepatotoxicity is the most common reason cited for withdrawal of already approved drugs from market and accounts more than 50 percent cases acute liver failure in United States. Ethanol (EtOH) causes a further substantial amount insufficiencies world wide. The current thesis was focused on mechanisms behind caused by these agents. Using rat vivo model alcoholic disease (ALD) it found that cytokine chemokine levels blood accompanied fluctuating EtOH, indicating they are directly influenced absolute EtOH concentration. During early phases ALD this model, strong initial Th1 response observed as revealed increased well transcription factor mRNAs, followed downregulation, whereas Th2 decreased over entire treatment period four weeks. We supplementation with antioxidant NAC to ethanol treated animals decreases severity damage somewhat inflammatory mediated TNFα. also diminished ethanol-induced formation protein adducts lipid peroxidation products like MDA HNE. Also, antibodies against neo-antigens formed MDA, HNE HER lowered. In order study influence oxidative stress we utilized transgenic mouse overexpressing human form CYP2E1. Pathological changes were significantly after treatment, principal component analysis showed among parameters influencing total pathology score, paranitrophenol activity mirroring CYP2E1 activity, had highest impact. Analysis 39,000 gene transcripts expression several genes previously known be associated TNFα mice. show cytokeratins 8 18, importance Mallory bodies, correlated highly score. results strongly support view an important role suggest cytokeratin can used marker ALD. There many different models available toxicity vitro, major drawback low predictability. hepatoma cell line B16A2 differentiates spontaneously long term confluent growth, into mature hepatocyte phenotype. developed co-culture system using cells monocytes that, compared single cultures, co-cultures cytotoxicity elevated mitochondrial troglitazone rosiglitazone without effect. data underline vitro harboring types studies drug hepatotoxicity.