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[摘要]
目的 通过连续28 d ig给予昆明小鼠大黄素,进而对其全身毒性和潜在的肝、肾毒性进行评价。方法 40只雄性昆明小鼠随机分成溶媒对照组(0.5% CMC-Na)和大黄素低、中、高剂量(100、300、600 mg/kg)组,最初的最高给药剂量为1 000 mg/kg,从给药第6天起将给药剂量调整为600 mg/kg,每组10只,连续给药28 d后进行解剖,给药后第57天进行恢复期解剖。给药后观察动物的大体症状,并进行体质量和肝、脾、肾、肾上腺及肠系膜淋巴结质量的测定、血清生化指标检测,以及大体和组织病理学检查。结果 给药结束,与溶剂对照组比较,大黄素高剂量组动物的平均体质量在试验的第3、7、10、14、17、21、28天显著降低(P<0.05、0.01、0.001);中、高剂量组动物血清丙氨酸氨基转移酶(ALT)水平升高,低、中剂量组动物血清天冬氨酸氨基转移酶(AST)水平升高,未见统计学的显著性差异,低、中、高剂量组的其他血清生化指标均未见明显变化;低、中、高剂量组绝对脏器质量及脏器指数均未见统计学的显著性差异。试验期间高剂量组共有6只动物死亡。死亡动物大体剖检可见脾体积减小,胸腺消失。死亡动物肝镜检可见轻度肝细胞坏死、轻度肝细胞变性/坏死伴炎性细胞浸润,以及极轻度色素沉着;肾镜检可见轻度肾小管变性/坏死、轻度肾小管变性/再生,以及轻度色素沉着;脾镜检可见轻度淋巴细胞数目减少和轻度易染体巨噬细胞增多。各组计划剖检动物大体检查未见异常。高剂量组动物肝镜检可见极轻度至轻度色素沉着;肾镜检可见极轻度至轻度色素沉着、极轻度至轻度肾小管变性/再生;胆囊镜检可见极轻度至轻度透明变性、轻度胆囊结石及轻度炎性细胞浸润(中性粒细胞为主)。结论 高剂量的大黄素可对动物产生明显的全身毒性作用,并可造成肝、肾、胆囊、脾损伤,大黄素的胆囊毒性为研究大黄素的肝、胆毒性机制提供新的思路和方向。
[Key word]
[Abstract]
Objective To evaluate the systemic toxicity and potential hepatotoxicity and nephrotoxicity of emodin monomer in Kunming mice by ig administration for 28 days. Methods 40 male Kunming (KM) mice were randomly divided into vehicle control group (0.5% CMC-Na), low dose (100 mg/kg emodin monomer), medium does (300 mg/kg emodin monomer) and high dose (1000 mg/kg emodin monomer, which was adjusted to 600 mg/kg after administrating on day 6), with 10 animals per group. Clinical symptoms of animals were observed after administration, and body weight and organ weights (include liver, spleen, kidney, adrenal gland and mesenteric lymph node), serum biochemical indicators were measured and detected, as well as gross and histopathological examination after administration. Results At the end of dosing, the mean body weight in the high dose group was significantly reduced on day 3, 7, 10, 14, 17, 21, and 28 of the experiment with a high statistical significance. There was no statistically significant difference in serum ALT levels in the middle dose and high dose groups and also in serum AST levels in the low dose group and the middle dose group. No significant change was observed in other serum biochemical indicators in the low dose group, medium dose group and high dose group. There was no statistically significant difference in absolute organ weight or relative organ/ body weight ratio in the low dose group, the medium dose group and the high dose group.A total of 6 animals in the high dose group died during the experiment. The spleen was decreased in size and the thymus was disappeared in the dead animals. Microscopic examination of the dead animals showed mild hepatocyte necrosis and mild hepatocyte degeneration/necrosis with inflammatory cell infiltration, as well as mild pigmentation; mild tubular degeneration/necrosis and mild tubular degeneration/regeneration are seen in the kidneys, as well as mild pigmentation; mild decreased lymphocyte number and mild increased number of tingible body macrophages were observed in the spleen. No abnormalities were found in the planned necropsy of each group. Microscopic examination showed minimal to mild pigmentation in the liver, minimal to mild pigmentation and mild renal tubular degeneration/ regeneration, as well as minimal to mild hyalinosis, mild biliary calculus and mild inflammatory cell infiltration (mainly neutrophils) in the gallbladder in the high dose group. Conclusion High-dose emodin monomer could produce evident systemic toxicity, and cause damages in liver, kidney, gall bladder and spleen. The gallbladder toxicity of emodin provides a new idea and direction for studying the mechanism of hepatotoxicity and biliary toxicity of emodin.
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[基金项目]
国家自然科学基金资助项目(81503347);国家十三五“重大新药创制”专项课题(2018ZX09201017)