Differential in vivo genotoxicity of arsenic trioxide in glutathione depleted mouse bone marrow cells: expressions of Nrf2/Keap1/P62

Abstract

Generation of reactive oxygen species is one of the major contributors in arsenic-induced genotoxicity where reduced glutathione (GSH) could be an important determining factor. To understand the role of endogenous GSH, arsenic trioxide (As₂O₃) was administered in buthionine sulfoximine (BSO)- and N-acetyl-l-cysteine (NAC)-treated mice. As₂O₃-induced significant chromosome aberrations (CAs) in all treatment groups compared with the control. BSO-treated mouse bone marrow cells showed significant CAs at a dose of 2 mg As₂O₃ kg⁻¹ b.w. Similar induction was not evident at 4 mg As₂O₃ kg⁻¹ b.w. and exhibited antagonistic effect at 8 mg As₂O₃ kg⁻¹ b.w. To understand this differential effect, expression pattern of Nrf2 was observed. Nrf2 expression increased following As₂O₃ treatment in a dose-dependent manner up to 4 mg As₂O₃ kg⁻¹ b.w after which no further increase was noticed. NAC pre-treatment significantly reduced the extent of As₂O₃-induced CAs suggesting the protective role of endogenous GSH against arsenic-induced genotoxicity.

• Arsenic trioxide
• buthionine sulfoximine
• genotoxicity
• glutathione
• mouse bone marrow cells
• N-acetyl-l-cysteine

Acknowledgements

Ritu Srivastava is grateful to UGC-DAE-CSR Kolkata for research fellowship and UGC for BSR fellowship. Professor Shelley Bhattacharya gratefully acknowledges NASI for the Senior Scientist Platinum Jubilee Fellowship.

Declaration of interest

The authors are grateful to University Grants Commission (UGC) for the support under Centre for Advanced Studies (CAS) Scheme Phase II and UGC-Department of Atomic Energy (DAE)-Consortium for Scientific Research (CSR), Kolkata Centre for partially funding the present work (Project Sanction no. UGC-DAE-CSR-KC/CRS/2009/TE-06/1544 to AC). The authors declare that there are no conflicts of interests.