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.