Induction of CYP1A1 increases gefitinib-induced oxidative stress and apoptosis in A549 cells.

As the first selective EGFR tyrosine kinase inhibitor, gefitinib has been clinically demonstrated to be effective for certain cancer cell types with EGFR-active gene mutations. However, a number of gefitinib-associated adverse pulmonary events have been reported, which could lead to the discontinuation of gefitinib therapy. Although previous reports have implicated that CYP1A1-mediated bioactivation of gefitinib maybe a major reason for the pulmonary toxicity, the roles of CYP1A1 in gefitinib-associated toxicity and the related molecular mechanism have not been well-characterized. This study aimed to reveal whether the induction of CYP1A1 would contribute to the toxic effect of gefitinib in living cells and to investigate the underlying molecular mechanism. The results demonstrated that gefitinib led to the enhancement of the dose-dependent cytotoxicity and the percentage of gefitinib-induced apoptosis was significantly increased on CYP1A1-overexpressed A549 cells, which was accompanied with a substantial increase in the intracellular reactive oxygen species and a remarkable decrease in the mitochondrial membrane potential. These findings strongly suggest that CYP1A1 can enhance the cytotoxicity of gefitinib and gefitinib-induced oxidative stress, which may partially explain the occurrence of pulmonary toxicity in some patients administered with gefitinib.