Dilworth, Clive; (1998) Induction of the stress response in hepatocytes as a protective mechanism and its use as a marker of toxicity in vivo and in vitro. Doctoral thesis (Ph.D), UCL (University College London).

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Abstract

All prokaryotic and eukaryotic cells in response to stressful insults, such as chemical exposure or hyperthermic treatment upregulate a well conserved set of genes. These genes encode a family of proteins known as stress proteins whose induction is an adaptive response which serves to protect the cells by interacting with denatured or damaged proteins. The aim of the current thesis was to determine the effect of induction of stress proteins on the subsequent toxicity of chemicals in isolated hepatocytes. A further aim was to determine whether the induction of stress proteins following chemical exposure could be used as a sensitive marker of chemical exposure. These studies were performed in two hepatocyte models, hepatocyte monolayers and liver spheroids, and the hepatic effect was also determined in vivo. Hyperthermic treatment of hepatocytes had a bi-phasic effect on the toxicity of subsequent chemical exposure. Exposure of cells to chemicals immediately following hyperthermic treatment resulted in a sensitisation of the cells to the toxin. If the cells were allowed a recovery period prior to chemical exposure the hepatocytes became tolerant to the toxic actions of the chemicals. The reasons for this are thought to be alterations in stress protein and GSH levels. The use of stress proteins as markers was problematic as hepatocyte monolayers had elevated basal stress protein levels resulting in poor induction following chemical exposure. However, liver spheroids had low basal stress protein levels which were significantly induced following chemical exposure to a greater extent than the response observed in vivo. However, in all situations only certain stress proteins were induced following exposure to specific chemicals. Differences in the activation of the transcription factor responsible for stress protein induction (HSF-1) were thought to be responsible for these differences. Therefore, measurement of these components of stress response may not be an all encompassing marker of toxicity but may be of use in determining the toxicity of certain chemicals. However, it does not rule out the possibility that other components of the stress response may be of use as such a marker.

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