Abstract
To reduce the amount of laboratory animals which are used to analyze hepatotoxic properties of chemicals and drugs, the development of alternative in vitro models is necessary. Ideally these in vitro models reflect the in vivo toxicological response and cholestasis. In this study the protein expression in livers from C57BL/6 mice after cyclosporin A-induced cholestasis was analyzed. After 25 days of a daily cyclosporine A treatment the cholestatic phenotype was established. An in vitro to this in vivo study comparison was made by using the results of our previous studies with HepG2 and primary mouse hepatocytes. The in vivo proteomics data show cyclosporin Ainduced oxidative stress and mitochondrial dysfunction was actually induced, leading to a decreased mitochondrial ATP production and an altered urea cycle. These processes were also altered by cyclosporin A in the in vitro models HepG2 and primary mouse hepatocytes. In addition, detoxification enzymes like methyl- and glutathione-Stransferases were differentially expressed after cyclosporin A treatment. Changes in these detoxification enzymes were mainly detected in vivo, though primary mouse hepatocytes show a differential expression of some of these enzymes. By means of a functional classification of differentially expressed proteins we demonstrated similarities and differences between in vitro and in vivo models in the proteome response of cyclosporin A-induced hepatotoxicity.
Highlights
Novel drugs should be recognized as safe for human exposure
An in vitro-in vivo comparison of cyclosporin A (CsA)-induced protein expression profiles was established by comparing these results with the results from our previous in vitro studies with HepG2 and primary mouse hepatocytes [9,10] For this purpose, we analyzed the hepatic protein expression in C57BL/6 mice after CsA-induced cholestasis
The cholestatic phenotype was established after 25 days and confirmed by histopathology and serum parameters, which allowed us to search for cholestatic-specific mechanisms in vivo
Summary
Novel drugs should be recognized as safe for human exposure. With respect to drug-induced toxicity, hepatotoxicity is prominent, because most drugs are metabolized to be eliminated by the liver. The hepatotoxic properties of chemicals and drugs are usually analyzed in in vivo repeated-dose toxicity tests, which involve a high number of laboratory animals. To reduce the amount of laboratory animals, alternative in vitro models are currently developed and their screening properties evaluated [1,2,3]. These in vitro models reflect the in vivo toxicological response. By applying Omics technologies it is possible to measure similar endpoints of drug-induced changes between in vitro and in vivo which enable a global comparison of both models [4]
Sign-in/Register to view highlights & summary 
Published Version
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call