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两种具有抗乙酰胆碱酯酶活性的多金属氧酸盐的毒性评估

Toxicity evaluation of two polyoxotungstates with anti-acetylcholinesterase activity.

作者信息

Čolović Mirjana B, Medić Branislava, Ćetković Mila, Kravić Stevović Tamara, Stojanović Marko, Ayass Wassim W, Mougharbel Ali S, Radenković Miroslav, Prostran Milica, Kortz Ulrich, Krstić Danijela Z

机构信息

Department of Physical Chemistry, "Vinča" Institute of Nuclear Sciences, University of Belgrade, Serbia.

Department of Pharmacology, Clinical Pharmacology and Toxicology, Faculty of Medicine, University of Belgrade, Serbia.

出版信息

Toxicol Appl Pharmacol. 2017 Oct 15;333:68-75. doi: 10.1016/j.taap.2017.08.010. Epub 2017 Aug 19.

Abstract

A toxicity evaluation of two Keggin-type heteropolytungstates, K[TiPWO]·6HO and KH[SiVWO]·3HO, with different inhibitory potencies toward acetylcholinesterase activity (IC values of 1.04×10 and 4.80×10mol/L, respectively) was performed. Wistar albino rats were orally treated with single doses (5 and 50mg/kg) of both investigated compounds. The biochemical parameters of renal (serum urea and creatinine) and liver function (direct and total bilirubin, alanine transaminase, and aspartate aminotransferase) were determined after 24h and 14days. A histopathological analysis of liver tissue was carried out 14days after the polyoxotungstate administration. Both applied doses of the investigated compounds did not induce statistically significant alterations of the renal function markers. However, the polyoxotungstate treatment caused an increase in the activities of serum alanine transaminase and aspartate aminotransferase in a time- and concentration-dependent manner, although statistically significant changes in bilirubin concentrations were not observed. Furthermore, the detected hepatotoxic effect was confirmed by histhopathological analysis that suggested some reversible liver tissue damage two weeks after the treatment, especially in the case of KH[SiVWO]·3HO. Accordingly, the toxicity of these two polyoxotungstates with anti-acetylcholinesterase effect cannot be considered as a severe one, but their potential clinical application would require a more complex toxicological study.

摘要

对两种具有不同乙酰胆碱酯酶活性抑制效力(IC值分别为1.04×10和4.80×10mol/L)的Keggin型杂多钨酸盐K[TiPWO]·6H₂O和KH[SiVWO]·3H₂O进行了毒性评估。用单剂量(5和50mg/kg)的两种研究化合物对Wistar白化大鼠进行口服治疗。在24小时和14天后测定肾脏(血清尿素和肌酐)和肝功能(直接胆红素和总胆红素、丙氨酸转氨酶和天冬氨酸转氨酶)的生化参数。在施用多氧钨酸盐后第14天对肝脏组织进行组织病理学分析。所研究化合物的两种施用剂量均未引起肾功能标志物的统计学显著改变。然而,多氧钨酸盐处理以时间和浓度依赖性方式导致血清丙氨酸转氨酶和天冬氨酸转氨酶活性增加,尽管未观察到胆红素浓度的统计学显著变化。此外,组织病理学分析证实了检测到的肝毒性作用,表明治疗两周后肝脏组织有一些可逆性损伤,尤其是在KH[SiVWO]·3H₂O的情况下。因此,这两种具有抗乙酰胆碱酯酶作用的多氧钨酸盐的毒性不能被视为严重毒性,但它们潜在的临床应用需要更复杂毒理学研究。

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