Structure-activity relationship for the intrinsic hepatotoxicity of dinitrotoluenes

The relation of various structural parameters to hepatotoxic potential was investigated by using six dinitrotoluene (DNT) isomers and isolated rat hepatocyte suspensions as the biological test system. DNT-induced hepatotoxicity was found to correlate with an inhibition of protein synthesis and an increase in lactate dehydrogenase (LDH) release but not with lipid peroxidation. With each isomer, protein synthesis inhibition was the most sensitive indicator of cytotoxicity. Regardless of the indicator, ortho- and para-substituted isomers were more hepatotoxic at the same concentration than meta-substituted isomers. High-performance liquid chromatograms (HPLC) on samples at 4 h revealed significant quantities of reduced metabolites in the medium. However, increased lipid peroxidation (formation of thiobarbituric acid reactants or evolution of ethane) in the cells was not consistently demonstrated. log EC50 for protein synthesis inhibition and log EC20 for LDH release were linearly correlated with the C atomic charge on the ring carbons bearing the nitro substituents by using molecular orbital (MNDO calculations) theory. The relation was used to predict the hepatotoxic potentials of untested nitrotoluenes, and the predictions were verified to a first approximation by using three trinitrotoluene isomers.