学术
代谢活化在三氯乙烯对小鼠致敏及肝毒性中的作用
戴宇飞 李海山 孙耀峰 冷曙光 牛勇 程娟 张林媛 郑玉新
中国疾病预防控制中心职业卫生与中毒控制研究所,北京100050
摘 要:
目的 研究三氯乙烯（TCE）通过什么代谢通路活化后才具有致敏活性。方法 以TCE和细胞色素P450（CYP450）诱导剂（乙醇和苯巴比妥）分别及联合给小鼠染毒，测定血清中丙氨酸氨基转移酶（GPT）和天冬氨酸氨基转移酶（GOT）活性；分离脾细胞体外培养，采用噻唑兰（MTT）法测定TCE所致小鼠脾淋巴细胞特异性增殖反应和细胞毒性，并观察体外培养过程中加入代谢酶抑制剂SKF-525A和氨氧乙酸（AOAA）后对上述效应的影响。结果 TCE致敏组小鼠脾淋巴细胞与TCE共孵育后，细胞相对数（79±10）％明显高于溶剂对照组（63±11）％，差异有统计学显著性（P〈0．05），在培养液中加入β-裂合酶抑制剂AOAA后，这种抗原特异性淋巴细胞增殖反应消失；而乙醇诱导＋TCE组和苯巴比妥诱导＋TCE组小鼠脾淋巴细胞未出现TCE特异性增殖反应。溶剂对照组、TCE致敏组、乙醇诱导＋TCE组和苯巴比妥诱导＋TCE组小鼠脾淋巴细胞与TCE＋SKF共培养后，细胞相对数均明显高于TCE单独培养的淋巴细胞，差异有统计学显著性（P〈0．05）。乙醇诱导＋TCE组血清GPT活性（49．5±8．4）μmol·min^-1·L^-1和苯巴比妥诱导＋TCE组血清GPT，COT活性（47.3±9．9）和（170±36）μmol·min^-1·L^-1均明显高于溶剂对照组（34．7±2．1）和（117±34）μmol·min^-1·L^-1，差异有统计学显著性（P〈0．05），而TCE致敏组小鼠血清GPT和GOT活性与溶剂对照组相比均无显著性差异（P〉0．05）：结论 TCE谷胱甘肽结合通路的代谢产物-巯基烯酮类物质具有致敏活性，可能是TCE致敏小鼠的特异性半抗原，而TCE氧化通路的代谢产物是产生细胞毒性和肝损伤的主要物质，乙醇和苯巴比妥能够增加TCE的肝脏毒性。[著者文摘]
文章出处:
《中国药理学与毒理学杂志》-2005年19卷5期 -378-382页
栏目信息:
分 类 号:
文献标识码:
A
文章编号:
1000-3002（2005）05-0378-05
Effect of metabolic activation in allergic reaction and hepatoxicity induced by trichloroethylene
DAI Yu-Fei, LI Hai-Shan, SUN Yao-Feng, LENG Shu-Guang, NIU Yong, CHENG Juan, ZHANG Lin-Yuan, ZHENG Yu-Xin （National Institute for Occupational Health and Poison Control, Chinese Center for Disease Control and Prevention, Bering 100050, China）
Abstract:
AIM To investigate which metabolic pathway makes trichioroethylene （TCE） activated to induce allergic reaction. METHODS Female BALB/c mice pretreated with ethanol or phenobarbital （PB） were administered TCE for 6 weeks, the activities of aspartate aminotransferase （GOT） and alanine aminotransferase （GFF） in serum were measured as markers of hepatic damage. The TCE-specific lymphocytes proliferation and cytotoxicity of TCE and its metabolites were determined in cultured spleen lymphocytes exposed to TCE and CYP450 inhibitor SKF-525A or β-lyase inhibitor aminooxyacetic acid（AOAA） in vitro. RFSULTS In TCE-treated mice, the survival number of lymphocytes cultured with TCE was significantly higher than that in control group [（79±10）% vs （63±11）%, P〈0.051, while, the TCE-specific lymphocyte proliferation was disappeared when the β-lyase inhibitor AOAA was added in cultured mixture. In ethanol-pretreated and PB-pretreated mice, no obvious TCE-specific lymphocyte proliferation was found when cultured with TCE, TCE ＋ AOAA or TCE ＋ SKF. The survival rote of lymphocyte cultured with TCE ＋ SKF was significantly higher than that cultured with TCE alone in all 4 groups of mice（solvent control, TCE semsitized, ethanol ＋ TCE, PB ＋ TCE）. Moreover, the results showed that GPT activity in ethanol-pretreated [（49.5± 8.4） μmol·min^-1·L^-1] and both GPT and GOT activities in PB-pretreated groups [（47.3±9.9） and （170±36）μmol·min^-1·L^-1 respectively] were higher than that in control group [（34.7±2.1） and （117±34）μmol·min^-1·L^-1 respectively]. However, no obvious hepatotoxic effect was observed in TCE-treated animals. CONCLUSION Glutathione-dependent pathway of TCE metabolism may play an important role in allergic reaction induced by TCE, dichlorovinyl thiol- metabolite produced by β-lyase catalysis in this pathway could act as an effective immune hapten to stimulate the proliferation of hapten-specific lymphocytes in TCE-sensitized animals. The metabolites in oxidative pathway of TCE metabolism cause cytotoxicity and hepatic injury, ethanol and PB could enhance the hepatotoxic effects of TCE by induction of oxidative pathway.[著者文摘]
Key words:
trichloroethylene; sensitization; liver; toxicity; metabolism
基金资助:
国家自然科学基金资助项目（30271115）
更多>>免费文章
cqvip.com