Faculty of Pharmacy and Pharmaceutical Sciences, University of Alberta, Edmonton, Alberta, Canada.
Faculty of Pharmacy and Pharmaceutical Sciences, University of Alberta, Edmonton, Alberta, Canada.
Chem Biol Interact. 2022 Sep 1;364:110049. doi: 10.1016/j.cbi.2022.110049. Epub 2022 Jul 21.
Arsenic trioxide (ATO) has evolved from an environmental threat to a successful therapy for acute promyelocytic leukemia (APL) and probably for solid tumors in the future. However, its efficacy comes at a cost of multi-organ toxicity whose mechanism remains unresolved. Arsenicals have been reported to modulate cytochrome P450 1A (CYP1A) enzymes, thus modifying activation/detoxification of drugs/procarcinogens. Therefore, this study aimed to investigate the possible effects of ATO on CYP1A1 and CYP1A2, in absence and presence of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) using in vivo and in vitro models. For this purpose, C57BL/6 mice were intraperitoneally injected with 8 mg/kg ATO with or without 15 μg/kg TCDD for 6 and 24 h. Furthermore, HepG2 cells were treated with ATO (1, 5, and 10 μM) with or without 1 nM TCDD for 6 and 24 h. ATO significantly inhibited TCDD-mediated induction of CYP1A1/1A2 mRNA, protein, and activity in both models. ATO differentially modulated CYP1A1/1A2 basal levels in vivo. We also demonstrated that ATO downregulates CYP1A through inhibiting the transcriptional activation of its regulatory element at both basal and inducible levels. Additionally, ATO significantly induced mRNA and protein of heme oxygenase 1 (HMOX1) in vivo and in vitro. In HepG2 cells, inhibition of HMOX1 by tin (IV) mesoporphyrin (IX) (SnMP) resulted in a partial restoration of the TCDD-mediated induction of CYP1A1 activity that was inhibited by ATO co-exposure. Our findings show that ATO alters both constitutive and inducible CYP1A1/1A2 expressions through transcriptional and HMOX1-mediated post-translational mechanisms. This implies the possible involvement of ATO in clearance-related consequences for the substrates of these enzymes such as drug-drug interactions or suboptimal toxicant elimination.
三氧化二砷（ATO）已从环境威胁演变为急性早幼粒细胞白血病（APL）的成功治疗方法，并且可能在未来成为实体瘤的治疗方法。然而，其疗效是以多器官毒性为代价的，其机制仍未解决。已有报道称砷剂可调节细胞色素 P450 1A（CYP1A）酶，从而改变药物/前致癌物的激活/解毒。因此，本研究旨在使用体内和体外模型研究 ATO 对 CYP1A1 和 CYP1A2 的可能影响，包括在没有和存在 2,3,7,8-四氯二苯并-p-二恶英（TCDD）的情况下。为此，用 8mg/kg ATO 腹腔内注射 C57BL/6 小鼠，并用或不用 15μg/kg TCDD 处理 6 和 24 小时。此外，用 ATO（1、5 和 10μM）处理 HepG2 细胞，并用或不用 1nM TCDD 处理 6 和 24 小时。ATO 显著抑制了两种模型中 TCDD 介导的 CYP1A1/1A2 mRNA、蛋白和活性的诱导。ATO 在体内差异调节 CYP1A1/1A2 的基础水平。我们还证明 ATO 通过抑制其调节元件在基础和诱导水平上的转录激活来下调 CYP1A。此外，ATO 还显著诱导了体内和体外 HepG2 细胞中血红素加氧酶 1（HMOX1）的 mRNA 和蛋白。在 HepG2 细胞中，HMOX1 的抑制剂锡（IV）mesoporphyrin（IX）（SnMP）的抑制作用部分恢复了由 ATO 共暴露抑制的 TCDD 介导的 CYP1A1 活性的诱导。我们的研究结果表明，ATO 通过转录和 HMOX1 介导的翻译后机制改变 CYP1A1/1A2 的组成型和诱导型表达。这意味着 ATO 可能参与这些酶的底物的清除相关后果，例如药物相互作用或毒物消除不理想。
