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Shengwen Shen,¹ Jane Lee,² Xuejun Sun,² Hailin Wang,¹ Michael Weinfeld,² and X. Chris Le¹

¹Department of Public Health Sciences and Department of Laboratory Medicine and Pathology; and ²Department of Oncology, Faculty of Medicine and Dentistry, University of Alberta, Edmonton, Canada

Abstract
Background: Arsenite (iAs^III) 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 iAs^III on the formation of benzo[a]pyrene diol epoxide (BPDE) –DNA adducts.

Results: We found that pretreatment with iAs^III 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 iAs^III treatment, but none of these factors appeared to account for the enhanced formation of DNA adducts. However, we found that pretreatment with iAs^III increased the cellular uptake of BPDE in a dose-dependent manner.

Conclusions: Our results suggest that iAs^III 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.

Key words: arsenic, benzo[a]pyrene, cellular uptake, co-carcinogenicity, DNA adducts. Environ Health Perspect 114: 1832–1837 (2006) . doi:10.1289/ehp.9284 available via http://dx.doi.org/ [Online 18 August 2006]

Address correspondence to X.C. Le, Department of Public Health Sciences and Department of Laboratory Medicine and Pathology, Faculty of Medicine and Dentistry, University of Alberta, 10-102 Clinical Sciences Building, Edmonton, Alberta, Canada T6G 2G3. Telephone: (780) 492-6416. Fax: (780) 492-7800. E-mail: xc.le@ualberta.ca

This work was supported by the Natural Sciences and Engineering Research Council of Canada, National Cancer Institute of Canada, Terry Fox Foundation, Canadian Water Network, Alberta Health and Wellness, and Canada Research Chairs Program.

The authors declare they have no competing financial interests.

Received 22 April 2006 ; accepted 16 August 2006.