二甲基甲酰胺对C57BL/6雄性小鼠急性肝毒性效应研究  

Acute hepatotoxicity of N,N-dimethylformamide in C57BL/6 male mice

作　　者：管明月[1] 吴智君[1] 张蔓[1] 郑敏[1] 赵文锦[1] 王磊[1] 程娟[1] 

机构地区：[1]中国疾病预防控制中心职业卫生与中毒控制所毒理室,北京100050

出　　处：《现代预防医学》2017年第11期2023-2026,共4页Modern Preventive Medicine

基　　金：国家自然科学基金项目(No.81372963)

摘　　要：目的探讨N,N-二甲基甲酰胺(DMF)对C57BL/6雄性小鼠肝脏的急性毒性效应。方法 32只雄性C57BL/6小鼠随机分为4组,每组8只。2、3、4组单次经口染毒1 500 mg/kg(bw DMF后分别在24 h,48 h,72 h处死。1组为空白对照组。记录各组小鼠染毒前后的体重并计算肝脏系数。摘眼球取血并分析血生化指标,光镜下观察肝组织切片检查肝脏损伤情况;LC-MS/MS检测小鼠血液中N-甲基氨基甲酰加合物(NMHb)含量。结果与对照组相比,染毒后各组肝脏系数差异均有统计学意义(F=5.837,P<0.05)。24 h时血清丙氨酸氨基转移酶(ALT)水平升高且差异有统计学意义(F=17.173,P<0.05);肝脏出现多灶性水样变伴小的坏死灶,表现出较明显的肝脏毒性效应。48 h时毒性效应进一步加重,ALT、AST(天门冬氨酸转移酶)升至高峰(F=17.173,P<0.05;F=17.633,P<0.05),镜下呈弥漫性肝细胞坏死及炎细胞浸润等病理改变。染毒后72 h时毒性效应减轻,ALT、AST较48 h时有所下降,但与对照组比较差异仍有统计学意义(F=17.173,P<0.05;F=17.633,P<0.05);肝脏以弥漫性水样变和点状坏死为主,病变程度有所减轻。2、3、4组小鼠血液NMHb含量分别为18.56±9.60、22.35±7.66和19.55±3.56 nmol/g globin,1组无检出。结论 DMF可以引起C57BL/6雄性小鼠急性肝毒性损伤并在48h左右达到高峰;NMHb可以在DMF染毒小鼠血液样本中检出。Objective To investigate the acute hepatotoxicity produced by N, N -dimethylformamide （DMF） in C57BL/6 male mice. Methods A total of 32 C57BL/6 male mice were divided into four groups randomly. All subjects were weighted before treatment and after sacrifice. Meanwhile, the liver index of all subjects was calculated. Group 2,3 and 4 were sacrificed respectively at 24 h,48 h and 72 h after oral DMF exposure of 1500 mg/ kg. bw. Group 1 was a blank control. The blood was collected after plucking the eyeballs from 4 of 8 mice in each group for blood biochemistry analysis, including alanine aminotransferase （ ALT）, aspartate aminotransferase （ AST）, alkaline phosphatase （ ALP）, triglyceride （TG） and total bile acid （TBA）. The blood of another 4 mice was collected for NMI-Ib detecting by LC - MS/MS. The histopathological changes of the liver were observed via HE staining. Results Liver index of all three experimental groups was significantly higher than that of the control （F = 5. 837,P 〈 0.05 ）. At 24 h after exposure, the ALT was significantly higher （ F = 17. 173, P 〈 0.05 ; F = 17. 633 ,P 〈 0.05 ） and hydropic degeneration of liver indicated emergence of acute hepatotoxicity. ALT and AST remained increasing and up to peak value by the time of 48 h after exposure and the necrosis with neutrophil in filtration was observed. At 72 h,the AST and ALT decreased slighter than that of 48 h （ F = 17. 173,P 〈 0.05 ; F = 17. 633, P 〈 0.05）. Meanwhile, the liver histopathologic examination showed the hydropic degeneration and Kupffer cell proliferation. NMHb was detectable in all three DMF- exposed groups but was undetectable in the control group. Conclusion Acute hepatotoxicity can be caused by DMF in C57BL/6 male mice and get most obviously at about 48 - hr post - exposure. NMHb is detectable in DMF - exposed C57BL/6 male mice.

关 键 词：N N-二甲基甲酰胺 C57BL/6小鼠 肝毒性效应 N-甲基氨基甲酰加合物 

分 类 号：R114[医药卫生—卫生毒理学]