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小鼠染毒α-鹅膏毒肽尿中代谢及毒性特征

Toxicity and urinary metabolites of α-amanitin in mice

  • 摘要:
      目的   建立小鼠染毒α – 鹅膏毒肽21 d完整中毒模型,探讨小鼠尿中毒素代谢及毒性特征。
      方法   雄性小鼠20只,对照组(n = 5)和半数致死量(LD50)染毒组(n = 15),单次腹腔注射α – 鹅膏毒肽染毒。染毒后1~7 d,代谢笼收集尿液,通过液质联用法检测毒素;染毒后0~21 d,记录中毒症状、体重和死亡。21 d处死存活小鼠,测定肝肾重量、系数、生化、病理。
      结果  染毒后1~4 d,染毒小鼠尿液均可检出毒素,且第1 d排出毒素占1~7 d排出量的67 %~98.35 %。染毒后3~10 d,LD50组共死亡6只小鼠。染毒后21 d,与对照肾脏重量(0.59 ± 0.05)g、肾脏系数(1.49 ± 0.09) %、肌酐(11.30 ± 7.60)µmol/L、碱性磷酸酶(78.00 ± 13.20)U/L相比,LD50组存活小鼠均有显著改变(0.48 ± 0.05) g、(1.35 ± 0.11) %、(18.25 ± 8.80) µmol/L、(111.50 ± 32.30) U/L,P < 0.05,且肾脏病变部位主要为肾脏皮质外层结构,表现为肾小管病变及大量粉染蛋白管型。
      结论  小鼠α – 鹅膏毒肽中毒早期尿液(1~4 d)可检测到毒素,中毒晚期以肾损伤为主。

     

    Abstract:
      Objective  To explore toxicity and urinary metabolites of α-amanitin in mice with a 21-day toxicological experiment.
      Methods  Twenty ICR male mice were randomly divided into a control (n = 5) and three median lethal dose (LD50) groups (5 in each group) with a single intraperitoneal injection of α-amanitin at doses of 0.25, 0.35, and 0.5 mg/kg·bw. Daily urine excretion of the mice was collected from 1st to 7th day after the injection for detection of toxins with liquid chromatography-mass spectrometry. Poisoning symptoms, body weight, and death of the mice were recorded during the 21-day experiment. By the end of the observation, all mice were sacrificed for determinations of liver/kidney weight and organ coefficient, blood biochemical indicators and pathological examination.
      Results  Urinary α-amanitin was detected in all mice of dose groups for 4 days after the toxic treatment and the urinary excretion of α-amanitin in the 1st day accounted for 67.00 % – 98.35% of total urinary excretion within 7 days after the intoxication. Six deaths were observed in the mice of dose groups from 3rd to 10th day after the toxic treatment. Compared to those in the control mice, significantly decreased kidney weight (0.48 ± 0.05 vs. 0.59 ± 0.05 g) and coefficient (1.35 ± 0.11% vs. 1.49 ± 0.09%) but increased serum creatinine (18.25 ± 8.80 vs. 11.30 ± 7.60 µmol/L) and alkaline phosphatase (111.50 ± 32.30 vs. 78.00 ± 13.20 U/L) were detected in the surviving mice of dose groups at the end of experiment (P < 0.05 for all); kidney pathological changes of the surviving mice were also observed mainly in renal cortex, including renal tubular lesion and a large amount of protein cast.
      Conclusion  In mice, urinary excretion of α-amanitin could be detected in the early intoxication stage (1st – 4th day) and kidney injury is a main toxic effect in late stage of intoxication.

     

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