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Studies have been carried out in rats in vivo and in isolated hepatocytes from the same strain of rat in vitro using the hepatotoxicant hydrazine as a model compound. These studies have shown that a number of biochemical changes occur and are measurable in both systems. However, despite measuring the same parameters in each system, the effects do not necessarily show a quantitative or qualitative correlation. Thus depletion of glutathione and ATP occurred in both systems but required a much higher concentration in vitro. The effects on more liver-specific parameters such as triglyceride, citrulline and taurine levels in vivo were different or not observed in vitro and the inhibition of urea synthesis and cytotoxicity in vitro were not observed in vivo, although these endpoints are more relevant markers of hepatic effects. Inhibition of protein synthesis proved to be the marker that showed the best correlation, occurring at a similar concentration in vitro as in vivo, although not to the same extent. The importance of identifying specific endpoints of toxicity, the problems of comparing in vivo with in vitro data and the limitations in their interpretation are highlighted by the data presented. A knowledge of the underlying mechanisms of toxicity will clearly facilitate the design and interpretation of specific in vitro biomarkers. |
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