Heat shock response and cytotoxicity in C6 rat glioma cells: structure-activity relationship of different alcohols

In C6 rat glioma cells, the n-alcohols methanol, ethanol, propanol, and butanol and the aromatic alcohol phenol all induce heat shock proteins (HSPs) of high molecular mass (68, 70, 90, and 110 kDa) when applied for 1 hr. The lowest alcohol concentrations that induce HSP synthesis cause about 20% cell death, as determined by neutral red assay. HSP induction thus occurs at alcohol concentrations close to the highest tolerable dose. The cytotoxicity and the potential of alcohols to induce the synthesis of HSPs increase with chain length and are correlated with the lipophilicity of the alcohols. A clear structure-activity relationship is observed for both parameters. A calculation of the putative membrane concentrations of these alcohols reveals that cytotoxic effects (50% cell death) occur at nearly the same membrane concentration (approximately 0.2 M). This also holds true for the lowest HSP 68-inducing alcohol concentrations, but at a lower concentration (approximately 0.12 M). The activities of major proteinases are affected by both heat shock and alcohols. The effects of alcohols also depend on the lipophilicity of the alcohols. Effective concentrations again are close to the highest tolerable dose. The stress reactions measured in terms of significant changes in HSP synthesis and proteinase activity provide information about the mechanisms by which toxic agents act on the cell.