Predicting oxidative stress induced by organic chemicals by using quantitative Structure-Activity relationship methods

Cellular exposure to xenobiotic human-made products will lead to oxidative stress that gives rise to DNA damage, as well as chemical or mechanical damage. Distinguishing the chemicals that will induce oxidative stress and predicting their toxicity is necessary. In the present study, 4270 compounds in the ARE-bla assay were investigated to predict active and inactive compounds by using simple algorithms, namely, recursive partitioning (RP) and binomial logistic regression, and to develop the quantitative structure-activity relationship (QSAR) models of chemicals that activate the ARE pathway to induce oxidative stress and exert toxic effects on cells. A decision tree based on scaffold-based fragments obtained through RP analysis showed the best identification accuracy. However, the overall identification accuracy of this model for active compounds was unsatisfactory due to limited fragments. Furthermore, a binomial logistic regression model was developed from 638 active compounds and 3632 inactive chemicals. The model with a cutoff of 0.15 could predict chemicals that were active or inactive with the prediction accuracy of 69.1%. Its area under the receiver operating characteristic (ROC) curve metric (AUROC) was 0.762, which indicated the acceptable predictive ability of this model. The parameters nBM (number of multiple bonds) and H% (percentage of H atom) played dominant roles in the prediction of the activity (inactive or active) of chemicals. A global QSAR model was developed to predict the toxicity of active chemicals. However, the model displayed an unsatisfactory result with R-2 = 0.316 and R-ext(2) = 0.090. Active chemicals were then classified on the basis of structure. A total of 79 compounds with carbon chains could be predicted with acceptable performance by using a QSAR model with six descriptors (R-2 = 0.722, R-ext(2) = 0.798, Q(Loo)(2) = 0.654, Q(Boot)(2) = 0.755, Q(ext)(2) = 0.721). The simple models established here contribute to efforts on identification compounds inducing oxidative stress and provide the scientific basis for risk assessment to organisms in the environment.