Quantitative structure-activity relationship (QSAR) modeling of the induction of oxidative stress in primary rat hepatocytes by halogenated aliphatics

Oxidative stress has a role in the mechanism of toxicity for a number of xenobiotic compounds, whether by production of free radicals or by depletion of cellular antioxidant capacity. Volatile halogenated aliphatic compounds are among those chemicals that cause oxidative stress. One can identify relationships between the potential of these chemicals to elicit certain biological responses and their specific chemical properties, such as molecular orbital energies or partition coefficients. Quantitative structure-activity relationship (QSAR) models have not been previously reported for the potential of a series of brominated and chlorinated 1- and 2-carbon aliphatics (methanes/ethanes) to induce multiple oxidative stress biomarkers in primary rat hepatocytes. By utilizing a novel in vitro methodology to expose cultures of primary hepatocyte cultures to volatile chemicals, biological responses were assessed following exposures to halogenated aliphatics. This assessment included measurement of oxidative damage, as well as antioxidant capacity. Assays were used for lipid peroxidation, catalase enzyme, reactive oxygen species, thiol status, and cytotoxicity. For these halogenated aliphatic compounds, semi-empirical molecular orbital methods were used for calculating the physical/chemical properties used as descriptors in the QSAR models. A preliminary QSAR model was derived for the cytotoxicity of six chemicals that had been selected based on their published toxicity. This preliminary model was used to select the rest of the 14 study chemicals, 5 of which were not used in the full QSAR model development, but as a validation set for those models. Following experimental determination of all of the toxicity endpoints, QSAR models were developed for all 6 of the endpoints using the 15 of the model-building chemicals. The toxicity values for the validation set were calculated and then compared to their experimentally-derived values. Further modeling focused on describing the toxicities of the subset of methanes from the full set. The results show that certain descriptors, such as the molecular orbital energies, bond lengths, and molecular size were quantitatively correlated with the induction of oxidative stress or cytotoxicity by halogenated aliphatics in primary rat hepatocytes.