Elevation of cellular BPDE uptake by human cells: A possible factor contributing to co-carcinogenicity by arsenite

Abstract

Background: Arsenite (iAsIII) can promote mutagenicity and carcinogenicity of other carcinogens. Considerable attention has focused on interference with DNA repair by inorganic arsenic, especially the nucleotide excision repair (NER) pathway, whereas less is known about the effect of arsenic on the induction of DNA damage by other agents. Objectives: We examined how arsenic modulates DNA damage by other chemicals. Methods: We used an NER-deficient cell line to dissect DNA damage induction from DNA repair and to examine the effects of iAsIII on the formation of benzo[a]pyrene diol epoxide (BPDE -DNA adducts. Results: We found that pretreatment with iAsIII at subtoxic concentrations (10 μM) led to enhanced formation of BPDE-DNA adducts. Reduced glutathione levels, glutathione S-transferase activity and chromatin accessibility were also measured after iAsIII treatment, but none of these factors appeared to account for the enhanced formation of DNA adducts. However, we found that pretreatment with iAsIII increased the cellular uptake of BPDE in a dose-dependent manner. Conclusions: Our results suggest that iAsIII enhanced the formation of BPDE-DNA adducts by increasing the cellular uptake of BPDE. Therefore, the ability of arsenic to increase the bioavailability of other carcinogens may contribute to arsenic co-carcinogenicity.