Acrolein- and 4-Aminobiphenyl-DNA adducts in human bladder mucosa and tumor tissue and their mutagenicity in human urothelial cells
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Hyun-Wook Lee1,*, Hsiang-Tsui Wang1,*, Mao-wen Weng1, Yu Hu1, Wei-sheng Chen1, David Chou1, Yan Liu2, Nicholas Donin2, William C. Huang2, Herbert Lepor2, Xue-Ru Wu2, Hailin Wang3, Frederick A. Beland4 and Moon-shong Tang1
1 Department of Environmental Medicine, New York University School of Medicine, Tuxedo Park, New York
2 Department of Urology, New York University School of Medicine, New York, New York
3 The State Key Laboratory of Environmental Chemistry and Ecotoxicology, Research Center for Eco-Environmental Sciences, Chinese Academy of Sciences, Beijing 100085, China
4 Division of Biochemical Toxicology, National Center for Toxicological Research, Jefferson, AR
* These two authors contribute equally to this research
Moon-shong Tang, email:
Keywords: Bladder cancer, 4-aminobiphenyl, Acrolein, DNA repair, Mutagenesis
Received: April 10, 2014 Accepted: May 6, 2014 Published: May 7, 2014
Tobacco smoke (TS) is a major cause of human bladder cancer (BC). Two components in TS, 4-aminobiphenyl (4-ABP) and acrolein, which also are environmental contaminants, can cause bladder tumor in rat models. Their role in TS related BC has not been forthcoming. To establish the relationship between acrolein and 4-ABP exposure and BC, we analyzed acrolein-deoxyguanosine (dG) and 4-ABP-DNA adducts in normal human urothelial mucosa (NHUM) and bladder tumor tissues (BTT), and measured their mutagenicity in human urothelial cells. We found that the acrolein-dG levels in NHUM and BTT are 10-30 fold higher than 4-ABP-DNA adduct levels and that the acrolein-dG levels in BTT are 2 fold higher than in NHUM. Both acrolein-dG and 4-ABP-DNA adducts are mutagenic; however, the former are 5 fold more mutagenic than the latter. These two types of DNA adducts induce different mutational signatures and spectra. We found that acrolein inhibits nucleotide excision and base excision repair and induces repair protein degradation in urothelial cells. Since acrolein is abundant in TS, inhaled acrolein is excreted into urine and accumulates in the bladder and because acrolein inhibits DNA repair and acrolein-dG DNA adducts are mutagenic, we propose that acrolein is a major bladder carcinogen in TS.
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