OBJECTIVE To evaluate the effects of phthalic acid esters(PAEs)on the expression of heme oxygenase-1(HO-1)in HepG2 cells,and to construct an HO-1-based three-dimensional quantita-tive structure-activity relationship(3D-QSAR)model.METHODS ① HepG2 cells were treated with seven types of PAEs:di-(2-ethylhexyl)phthalate(DEHP),di-n-octyl phthalate(DnOP),dimethyl phthalate(DMP),diethyl phthalate(DEP),dihexyl phthalate(DHXP),dimethylglycol phthalate(DMEP),and dibutyl phthalate(DBP),at final concentrations of 0(DMSO,solvent control),0.062 5,0.125,0.25,0.5 and 1 mmol·L-1(n=6)for 48 h at 37℃.The expression level of HO-1 was measured by Western blotting.② A 3D-QSAR model was constructed using comparative molecular similarity indices analysis(CoMSIA)based on the measured HO-1 levels.The applicability domain(AD)of the model was evaluated using the leverage method.Model fitting quality and predictive ability were evaluated via the KNIME Enalos+node to verify model stability.Additionally,molecular docking was performed to validate the binding interactions between PAEs and HO-1.RESULTS ① Compared with the solvent control group,48 h of exposure to 0.062 5 mmol·L-1 PAEs(DMP,DMEP,DEHP,DnOP and DEP)significantly increased HO-1 protein expressions,while 1 mmol·L-1 PAEs(DMP,DBP,DnOP,DEP and DHXP)significantly suppressed HO-1 expressions.② The 3D-QSAR model showed a non-cross-validated coefficient(R2)of 0.996 and a cross-validated coefficient(Q2)of 0.548.All the seven PAEs in the 3D-QSAR model were within the applicability domain(AD)and passed external validation.Molecular docking results indi-cated that DBP,DnOP,DEHP and DHXP exhibited stronger binding affinities to HO-1.CONCLUSION Forty-eight hours of exposure of HepG2 cells to 1 mmol·L-1 PAEs can significantly suppress HO-1 expres-sions.The 3D-QSAR model established in this study provides a potential tool for predicting the HO-1-related toxic effects of novel PAEs.

OBJECTIVE To evaluate the effects of phthalic acid esters(PAEs)on the expression of heme oxygenase-1(HO-1)in HepG2 cells,and to construct an HO-1-based three-dimensional quantita-tive structure-activity relationship(3D-QSAR)model.METHODS ① HepG2 cells were treated with seven types of PAEs:di-(2-ethylhexyl)phthalate(DEHP),di-n-octyl phthalate(DnOP),dimethyl phthalate(DMP),diethyl phthalate(DEP),dihexyl phthalate(DHXP),dimethylglycol phthalate(DMEP),and dibutyl phthalate(DBP),at final concentrations of 0(DMSO,solvent control),0.062 5,0.125,0.25,0.5 and 1 mmol·L-1(n=6)for 48 h at 37℃.The expression level of HO-1 was measured by Western blotting.② A 3D-QSAR model was constructed using comparative molecular similarity indices analysis(CoMSIA)based on the measured HO-1 levels.The applicability domain(AD)of the model was evaluated using the leverage method.Model fitting quality and predictive ability were evaluated via the KNIME Enalos+node to verify model stability.Additionally,molecular docking was performed to validate the binding interactions between PAEs and HO-1.RESULTS ① Compared with the solvent control group,48 h of exposure to 0.062 5 mmol·L-1 PAEs(DMP,DMEP,DEHP,DnOP and DEP)significantly increased HO-1 protein expressions,while 1 mmol·L-1 PAEs(DMP,DBP,DnOP,DEP and DHXP)significantly suppressed HO-1 expressions.② The 3D-QSAR model showed a non-cross-validated coefficient(R2)of 0.996 and a cross-validated coefficient(Q2)of 0.548.All the seven PAEs in the 3D-QSAR model were within the applicability domain(AD)and passed external validation.Molecular docking results indi-cated that DBP,DnOP,DEHP and DHXP exhibited stronger binding affinities to HO-1.CONCLUSION Forty-eight hours of exposure of HepG2 cells to 1 mmol·L-1 PAEs can significantly suppress HO-1 expres-sions.The 3D-QSAR model established in this study provides a potential tool for predicting the HO-1-related toxic effects of novel PAEs.