Modulation of aryl hydrocarbon receptor-regulated enzymes by trimethylarsine oxide in C57BL/6 mice: In vivo and in vitro studies

Abstract

Arsenic is a worldwide environmental pollutant that is associated with skin and several types of internal cancers. Recent reports revealed that arsenic biomethylation could activate the toxic and carcinogenic potential of arsenic. Therefore, we investigated the effect of trimethylarsine oxide (TMAO) on the activation of AhR-regulated genes in vivo and in vitro. In vivo, C57BL/6 mice received TMAO (13mg/kg i.p.) with or without the prototypical AhR ligand, TCDD (15μg/kg), then the livers were harvested at 6 and 24h post-treatment. In vitro, isolated hepatocytes from C57BL/6 mice were treated with TMAO (5μM) in the absence and presence of TCDD (1nM) for 6 and 24h. Our in vivo results demonstrated that, TMAO alone increased Cyp1a1, Cyp1a2, Cyp1b1, Nqo1, Gsta1, and Ho-1 at mRNA level. Upon co-exposure to TMAO and TCDD, TMAO potentiated the TCDD-mediated induction of Cyp1a1, Cyp1b1, and Nqo1 mRNA levels. Western blotting revealed that, TMAO alone increased Cyp1a1, Cyp1a2, Nqo1, Gsta1/2, and Ho-1 protein levels, and potentiated the TCDD-mediated induction of Cyp1a1 and Cyp1b1 protein level. In addition, TMAO alone significantly increased Cyp1a1, Cyp1a2, Nqo1, Gst, and Ho-1 activities and significantly potentiated the TCDD-mediated induction of Cyp1a1 activity. At the in vitro level, TMAO induced Cyp1a1 and potentiated the TCDD-mediated induction of Cyp1a1 at mRNA, protein and activity levels. In addition, TMAO increased the nuclear localization of AhR and AhR-dependent XRE-driven luciferase activity. Our results demonstrate that the TMAO, modulates AhR-regulated genes which could potentially participate, at least in part, in arsenic induced toxicity and carcinogenicity.

Keywords: AhR; Carcinogenesis; Cyp1a1; Cyp1a2; Cyp1b1; Gst; Ho-1; Nqo1; Trimethylarsine oxide.