Influence of small doses of various drug vehicles on acetaminophen-induced liver injury
Influence of small doses of various drug vehicles on acetaminophen-induced liver injury
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DOI：
10.1139/y10-065
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发表时间：
2010-10-01
影响因子：
2.1
通讯作者：
Culo, Filip
中科院分区：
文献类型：
--
作者：
Kelava, Tomislav;Cavar, Ivan;Culo, Filip
药物载体的生物学效应经常被忽视，经常导致对乙酰氨基酚诱导的肝损伤评估中的伪影。因此，我们决定研究二甲基亚砜、二甲基甲酰胺、丙二醇、乙醇和吐温20对对乙酰氨基酚诱导的肝损伤的影响。C57 BL/6雄性小鼠接受特定药物媒介物（0.6或0.2mL/kg，i. p.）对乙酰氨基酚给药前30分钟（300 mg/kg，腹膜内）。对照小鼠仅接受溶剂。通过测定血浆丙氨酸氨基转移酶浓度和观察肝组织病理学变化来评估肝损伤。还原型谷胱甘肽（GSH）水平通过测量总非蛋白肝硫代磷酸酯来评估。二甲亚砜和二甲基甲酰胺（两种剂量）几乎完全消除了对乙酰氨基酚的毒性。较高剂量的丙二醇（0.6 mL/kg）具有明显的保护作用，但较低剂量（0.2 mL/kg）仅具有轻微的保护作用。这些溶剂也减少了对乙酰氨基酚诱导的GSH消耗。二甲基甲酰胺是保护时，给予对乙酰氨基酚给药前2小时或1小时后，但无效，如果给予对乙酰氨基酚后2.5小时。较高剂量（0.6 mL/kg）的乙醇具有部分保护作用，而较低剂量（0.2 mL/kg）的乙醇以及任何剂量的吐温20均无影响。溶剂（0.6 mL/kg）本身均无肝毒性，在D-半乳糖胺和脂多糖引起的肝损伤模型中均无保护作用。
The biological effects of drug vehicles are often overlooked, often leading to artifacts in acetaminophen-induced liver injury assessment. Therefore, we decided to investigate the effect of dimethylsulfoxide, dimethylformamide, propylene glycol, ethanol, and Tween 20 on acetaminophen-induced liver injury. C57BL/6 male mice received a particular drug vehicle (0.6 or 0.2 mL/kg, i.p.) 30 min before acetaminophen administration (300 mg/kg, i.p.). Control mice received vehicle alone. Liver injury was assessed by measuring the concentration of alanine aminotransferase in plasma and observing histopathological changes. The level of reduced glutathione (GSH) was assessed by measuring total nonprotein hepatic sulfhydrils. Dimethylsulfoxide and dimethylformamide (at both doses) almost completely abolished acetaminophen toxicity. The higher dose of propylene glycol (0.6 mL/kg) was markedly protective, but the lower dose (0.2 mL/kg) was only slightly protective. These solvents also reduced acetaminophen-induced GSH depletion. Dimethylformamide was protective when given 2 h before or 1 h after acetaminophen administration, but was ineffective if given 2.5 h after acetaminophen. Ethanol at the higher dose (0.6 mL/kg) was partially protective, whereas ethanol at the lower dose (0.2 mL/kg) as well as Tween 20 at any dose had no influence. None of the vehicles (0.6 mL/kg) was hepatotoxic per se, and none of them was protective in a model of liver injury caused by D-galactosamine and lipopolysaccharide.