Faculty of Pharmacy and Pharmaceutical Sciences, University of Alberta, Edmonton, Alberta, Canada; Faculty of Pharmacy, Tanta University, Tanta, Gharbia, Egypt.
Faculty of Pharmacy and Pharmaceutical Sciences, University of Alberta, Edmonton, Alberta, Canada.
Toxicol Lett. 2024 Apr;394:32-45. doi: 10.1016/j.toxlet.2024.02.007. Epub 2024 Feb 24.
Dimethylmonothioarsinic acid (DMMTA), a pentavalent thio-arsenic derivative, has been found in bodily fluids and tissues including urine, liver, kidney homogenates, plasma, and red blood cells. Although DMMTA is a minor metabolite in humans and animals, its substantial toxicity raises concerns about potential carcinogenic effects. This toxicity could be attributed to arsenicals' ability to regulate cytochrome P450 1 A (CYP1A) enzymes, pivotal in procarcinogen activation or detoxification. The current study investigates DMMTA's impact on CYP1A1/2 expression, individually and in conjunction with its inducer, 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD). C57BL/6 mice were intraperitoneally injected with 6 mg/kg DMMTA, alone or with 15 μg/kg TCDD, for 6 and 24 h. Similarly, Hepa-1c1c7 cells were exposed to DMMTA (0.5, 1, and 2 μM) with or without 1 nM TCDD for 6 and 24 h. DMMTA hindered TCDD-induced elevation of Cyp1a1 mRNA, both in vivo (at 6 h) and in vitro, associated with reduced CYP1A regulatory element activation. Interestingly, in C57BL/6 mice, DMMTA boosted TCDD-induced CYP1A1/2 protein and activity, unlike Hepa-1c1c7 cells where it suppressed both. DMMTA co-exposure increased TCDD-induced Cyp1a2 mRNA. While Cyp1a1 mRNA stability remained unchanged, DMMTA negatively affected protein stability, indicated by shortened half-life. Baseline levels of CYP1A1/2 mRNA, protein, and catalytic activities showed no significant alterations in DMMTA-treated C57BL/6 mice and Hepa-1c1c7 cells. Taken together, these findings indicate, for the first time, that DMMTA differentially modulates the TCDD-mediated induction of AHR-regulated enzymes in both liver of C57BL/6 mice and murine Hepa-1c1c7 cells suggesting that thio-arsenic pentavalent metabolites are extremely reactive and could play a role in the toxicity of arsenic.
二甲基一硫代胂酸（DMMTA）是一种五价的硫代砷衍生物，已在尿液、肝脏、肾脏匀浆、血浆和红细胞等体液和组织中被发现。虽然 DMMTA 是人类和动物体内的一种次要代谢物，但它的高毒性引起了人们对其潜在致癌作用的关注。这种毒性可能归因于砷化合物调节细胞色素 P450 1A（CYP1A）酶的能力，这些酶在原致癌物激活或解毒中起着关键作用。本研究调查了 DMMTA 对 CYP1A1/2 表达的影响，单独作用以及与诱导剂 2,3,7,8-四氯二苯并二恶英（TCDD）共同作用时的影响。C57BL/6 小鼠经腹腔注射 6mg/kg 的 DMMTA，单独或与 15μg/kg 的 TCDD 一起注射，6 和 24 小时后收集样本。同样，Hepa-1c1c7 细胞暴露于 0.5、1 和 2μM 的 DMMTA 中，同时或不暴露于 1nM 的 TCDD 中，6 和 24 小时后收集样本。DMMTA 抑制了 TCDD 诱导的 Cyp1a1 mRNA 的升高，无论是在体内（6 小时）还是在体外，同时也降低了 CYP1A 调节元件的激活。有趣的是，在 C57BL/6 小鼠中，DMMTA 增强了 TCDD 诱导的 CYP1A1/2 蛋白和活性，而 Hepa-1c1c7 细胞中则抑制了它们。DMMTA 共同暴露增加了 TCDD 诱导的 Cyp1a2 mRNA。虽然 Cyp1a1 mRNA 的稳定性没有变化，但 DMMTA 对蛋白质的稳定性产生了负面影响，表现在半衰期缩短。在 DMMTA 处理的 C57BL/6 小鼠和 Hepa-1c1c7 细胞中，CYP1A1/2 mRNA、蛋白质和催化活性的基线水平没有明显变化。总的来说，这些发现首次表明，DMMTA 以不同的方式调节 TCDD 介导的 AHR 调节酶在 C57BL/6 小鼠肝脏和小鼠 Hepa-1c1c7 细胞中的诱导，表明五价硫代砷代谢物具有极高的反应性，可能在砷的毒性中发挥作用。
