Arsenic trioxide (ATO), one of the oldest and most frequently used poisons, is well-known in forensic science for inducing hepatotoxicity. The regulation of peroxisomal antioxidative enzyme catalase (CAT) involves intricate mechanisms at both transcriptional and post-transcriptional levels. However, the molecular mechanisms underlying the regulation of CAT gene expression in hepatic cells remain elusive. Furthermore, the regulation of CAT gene expression evident in animals administered with ATO is not well-explored, although several studies have revealed ATO-induced reductions in CAT enzymatic activity in rat livers. In this study, we revealed ATO-dependent reductions in CAT gene expression in both rat liver and Huh-7 human hepatoma cells. Our results indicate that the decline in CAT enzymatic activity can be attributed, at least in part, to the downregulation of its gene expression. The ATO-induced reduction in CAT expression was concurrent with the reduction in peroxisome proliferator-activated receptor-gamma (PPARγ) coactivator (PGC)-1α and inactivation of PPARγ, both considered as positive regulators of CAT gene expression. Moreover, antioxidant N-acetylcysteine (NAC) demonstrated the capability to alleviate the downregulation of CAT gene expression both and . Additionally, NAC played a role in alleviating ATO-induced hepatotoxicity, potentially by mitigating the transcriptional downregulation of the CAT gene. Altogether, these results indicate that ATO exerts toxicity by inhibiting the antioxidant defense mechanism, which may be useful for forensic diagnosis of arsenic poisoning and clinical treatment of mitigating ATO-induced hepatotoxicity.

中文翻译：

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N-乙酰半胱氨酸减轻三氧化二砷诱导的体外和体内肝过氧化氢酶基因表达降低


三氧化二砷 (ATO) 是最古老、最常用的毒物之一，在法医学中因引起肝毒性而闻名。过氧化物酶体抗氧化酶过氧化氢酶（CAT）的调节涉及转录和转录后水平的复杂机制。然而，肝细胞中 CAT 基因表达调控的分子机制仍不清楚。此外，虽然一些研究表明 ATO 诱导大鼠肝脏中 CAT 酶活性降低，但在施用 ATO 的动物中明显的 CAT 基因表达调节尚未得到充分探索。在这项研究中，我们揭示了大鼠肝脏和 Huh-7 人肝癌细胞中 CAT 基因表达的 ATO 依赖性降低。我们的结果表明，CAT 酶活性的下降至少部分归因于其基因表达的下调。 ATO 诱导的 CAT 表达减少与过氧化物酶体增殖物激活受体-γ (PPARγ) 共激活剂 (PGC)-1α 的减少和 PPARγ 失活同时发生，两者都被认为是 CAT 基因表达的正调节因子。此外，抗氧化剂 N-乙酰半胱氨酸 (NAC) 具有减轻 CAT 基因表达下调的能力。此外，NAC 在减轻 ATO 诱导的肝毒性方面发挥了作用，可能是通过减轻 CAT 基因的转录下调来实现的。总之，这些结果表明ATO通过抑制抗氧化防御机制发挥毒性，这可能有助于砷中毒的法医诊断和减轻ATO引起的肝毒性的临床治疗。