Development of In Vivo Biomarkers

The development of new biomarkers is based on an understanding of the physiologic functions of the liver and its response to injury. Drug exposure can alter the function of the liver and elicit injurious effects through different mechanisms. These mechanisms are becoming better understood and have been reviewed [3-5, 150, 

Apanel of in vivo biomarkers that refiects the different mechanisms of toxicity and that could be used to predict drug response in tissue would be invaluable in hepatotoxicity risk assessment. 

As an example, acetaminophen (APAP) in overdose has been used by several groups to identify hepatotoxicity biomarkers in mice. APAP-induced hepatotoxicity is characterized by hepatic centrilobular necrosis and hepatitis. APAP biotransformation by Phase I enzymes leads to the formation of the reactive metabolite N-acetyl-p-benzoquinone (NAPQI), which can deplete glutathione and form adducts with hepatic proteins (see Section 15.2). Protein adduction primes the hepatocytes for cytokines released by activated macrophages (Kupffer cells) and/or destructive insults by reactive nitrogen species. Although necrosis is recognized as the mode of cell death in APAP overdose, the precise mechanisms are still being elucidated [152]. 

The change in metabolic signature seen after drug treatment can be correlated with the magnitude of pathologic change, as described in toxicity studies by Baronas et al. and Hsieh et al. [148, 158]. 

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