Quantitative structure activity relationship for the acute cytotoxicity of 13 (bis)aziridinyl-benzoquinones: relation to cellular ATP depletion.

This study was performed to establish relationships between the structure of 2,5-bis(1-aziridinyl)-1,4-benzoquinones (BABQs) bearing different substituents at the 3- and 6-position and their acute toxic effects in rat hepatocytes. The cell viability, loss of cellular glutathione (GSH+GSSG) and loss of ATP were followed during 4 h of incubation of freshly isolated hepatocytes. The toxicity of these compounds (100 microM) was predicted better by their reactivity with GSH than by their redox cycling in rat liver microsomes. The time of 50% loss of viability (LT50) correlated very well with the time of 50% depletion of ATP (AT50). LT50 could be adequately predicted by using the electronic field parameter (Ftotal) describing the electron withdrawing or donating properties for all the substituents on the quinone-nucleus. 7-(Di)halogen-substituted BABQs that all very rapidly depleted cellular glutathione showed significant differences in AT50 as well as in LT50. This suggests that alterations in ATP levels are important for explaining the differences in cytotoxicity of these compounds.