Endoplasmic reticulum stress proteins in chemically mediated cytotoxicity

Endoplasmic reticulum (ER) stress proteins appear to play a role in chemically induced idiosyncratic and direct hepatocellular cytotoxicity. Circulating antibodies directed against ER stress proteins can be found in patients suffering from idiosyncratic adverse drug reactions (ADR) to halothane and sulfamethoxazole. What if any pathological role these proteins or antibodies against them play in these reactions is not clear. In contrast to the potential deleterious involvement of ER stress proteins in idiosyncratic adverse drug reactions, there is substantial evidence that the expression of these ER stress proteins can confer protection against direct toxicity in a number of cell lines. In spite of the central role of hepatocytes in drug metabolism resulting in high exposures to reactive intermediates (RI), no data exists on the protective role of ER stress proteins in hepatocytes.

Antibodies to ER stress proteins as well as organ toxicity are reported in immune-mediated ADR to sulfonamides and in the Long Evans Cinnamon (LEC) rat strain. It is not what, if any, role these circulating antibodies play in the accompanying toxicities. To investigate this, the onset of histological and biochemical evidence of liver damage in the LEC rat was compared temporally with the onset of circulating antibodies to ER proteins. In this study, toxicity was found to occur in the absence of these antibodies.

This work expands existing knowledge of the protective effects of ER stress proteins. The expression level of ER stress proteins was pharmacologically increased in the porcine kidney cell line LLC-PK1, the human hepatocyte cell line HepG2 and the rat hepatocyte cell line H4IIE. In contrast to the broad protection ER stress proteins confer to the kidney cell line LLC-PK1, it was demonstrated for the first time that ER stress provides only limited protection to human and rat hepatocytes. This limited hepatocellular protection was further explored by examining the effect of ER stress protein induction on calcium disturbances evoked by model toxins. The toxins differed in their effect on cytosolic calcium and pre-ER stress prevented the rise in cytosolic calcium. Finally, the protective effects of one specific ER stress protein, protein disulfide isomerase (PDI), was considered by developing kidney and hepatocyte cell lines that over-express the protein. In both transient and stable overexpressing cell lines, there was a production of the transfected mRNA, but there was no detectable increase in the expression of the PDI protein, therefore no conclusions could be drawn regarding the ability of this ER stress protein to confer cytoprotection against RI.