Hepatocytes Hepatotoxicity

In vitro studies on isolated cells including hepatocytes, erythrocytes, fibroblasts, and alveolar cells continue to demonstrate the specificity of action that these toxins have for liver cells (83,86,93). This specificity has led Aune and Berg (94) to use isolated rat hepatocytes as a screen for detecting hepatotoxic waterblooms of cyanobacteria. 

Fenvalerate inhibits intercellular communication between fibroblast cells and enhances the development of hepatocyte foci in rat liver at nonhepatotoxic dose levels. Chemicals that possess these properties are likely to be tumor promoters (Flodstrom et al. 1988). Fenvalerate alone induced no hepatotoxic effects in rat liver, as judged by transaminase activities and histology. However, some rats that were partially hepatectomized and insulted with nitrosodiethylamine — a carcinogen and tumor initiator — had significantly elevated numbers of liver foci after administrations of fenvalerate. This response suggests that fenvalerate is a potential tumor promoter (Flodstrom et al. 1988). 

Satoh, H. et al., Immunological studies on the mechanism of halothane-induced hepatotoxicity Immunohistochemical evidence of trifluoroacetylated hepatocytes, J. Pharmacol. Exp. Ther., 233, 857, 1985. 

Primary hepatocyte cultures have been used as a tool to predict the hepatotoxicity of many compounds such as nonsteroidal anti-inflammatory drugs (Castell et ah, 1988), psychotropic drugs (Boelsterli et ah, 1987), immunosuppressant drugs (Boelsterli et ah, 1988), and salicylates (Tolman et ah, 1978). Rat primary hepatocyte cultures have also been shown to be a good model for examining the mechanisms of metallothionein-induced tolerance to cadmium toxicity (Liu et ah,... 

Gomez-Lechon, M.J., Montoya, A., Lopez, P., Donato, T., Larrauri, A. and Castell, J.V (1988). The potential use of cultured hepatocytes in predicting the hepatotoxicity of xenobiotics. Xenobiotica 18 725-735. 

Guguen-Guillouzo, C., Gripon, P., Vandenbughe, Y., Lamballe, F., Rataanasavanh, D. and Guillouzo, A. (1988). Hepatotoxicity and molecular aspects of hepatocyte function in primary culture. Xenobiotica 18 773-783. 

The mechanism of carbon tetrachloride hepatotoxicity generally is viewed as an example of lethal cleavage, where the CCh— Cl bond is split in the mixed-function oxidase system of the hepatocytes. After this cleavage damage may occur directly from the free radicals (-CCl and -Cl) and/or from the formation of toxic metabolites such as phosgene." ... 

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]. 

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