Comparative analysis of the relationship between trichloroethylene metabolism and tissue-specific toxicity among inbred mouse strains: liver effects.
Comparative analysis of the relationship between trichloroethylene metabolism and tissue-specific toxicity among inbred mouse strains: liver effects.
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DOI：
10.1080/15287394.2015.958417
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发表时间：
2015
期刊：
影响因子：
--
通讯作者：
Rusyn I
中科院分区：
文献类型：
--
作者：
Yoo HS;Bradford BU;Kosyk O;Shymonyak S;Uehara T;Collins LB;Bodnar WM;Ball LM;Gold A;Rusyn I
三氯乙烯（TCE）是一种广泛使用的有机溶剂。虽然三氯乙烯被归类为对人类致癌，但我们对三氯乙烯代谢和毒性的个体间差异的理解仍存在很大差距，特别是在肝脏中。我们测试了一个假设，即小鼠肝脏中TCE的氧化代谢产物的量与肝脏特异性毒性相关。在亚急性（600 mg/kg/d; 5天; 7种近交系小鼠品系）和亚慢性（100或400 mg/kg/d; 1、2或4周; 2种近交系小鼠品系）设计中进行TCE口服给药。我们评估了血清和肝脏中细胞色素P450介导的氧化[三氯乙酸（TCA）、二氯乙酸（DCA）和三氯乙醇]和谷胱甘肽结合[S-（1，2-二氯乙烯基）-L-半胱氨酸和S-（1，2-二氯乙烯基）谷胱甘肽]形成TCE代谢物的菌株、剂量和时间依赖性之间的定量关系，以及各种肝毒性表型。在亚急性研究中，在血清和肝脏中观察到TCE代谢物量的菌株间变异性。未检测到肝脏中Cyp 2 e1蛋白水平的诱导。TCA和DCA的血清和肝脏水平与过氧化物酶体增殖标记基因Cyp 4a 10和Acox 1的转录增加相关，但与肝细胞增殖的诱导程度无关。在亚慢性研究中，尽管连续给药，但氧化代谢物的血清和肝脏水平随时间逐渐降低。Cyp 2 e1、Adh和Aldh 2的肝脏蛋白水平不受TCE处理的影响。虽然过氧化物酶体增殖标记基因的诱导幅度也下降，肝细胞增殖增加。这项研究提供了一个独特的机会，为TCE人类健康评估中的一些主要假设提供科学数据驱动的理由。
Trichloroethylene (TCE) is a widely used organic solvent. Although TCE is classified as carcinogenic to humans, substantial gaps remain in our understanding of inter-individual variability in TCE metabolism and toxicity, especially in the liver. We tested a hypothesis that amounts of oxidative metabolites of TCE in mouse liver are associated with liver-specific toxicity. Oral dosing with TCE was conducted in sub-acute (600 mg/kg/d; 5 days; 7 inbred mouse strains) and sub-chronic (100 or 400 mg/kg/d; 1, 2, or 4 weeks; 2 inbred mouse strains) designs. We evaluated the quantitative relationship between strain-, dose-, and time-dependent formation of TCE metabolites from cytochrome P450-mediated oxidation [trichloroacetic acid (TCA), dichloroacetic acid (DCA), and trichloroethanol] and glutathione conjugation [S-(1,2-dichlorovinyl)-L-cysteine and S-(1,2-dichlorovinyl)glutathione] in serum and liver, and various liver toxicity phenotypes. In sub-acute study, inter-strain variability in TCE metabolite amounts was observed in serum and liver. No induction of Cyp2e1 protein levels in liver was detected. Serum and liver levels of TCA and DCA were correlated with increased transcription of peroxisome proliferator-marker genes Cyp4a10 and Acox1, but not with degree of induction in hepatocellular proliferation. In sub-chronic study, serum and liver levels of oxidative metabolites gradually decreased over time despite continuous dosing. Liver protein levels of Cyp2e1, Adh and Aldh2 were unaffected by treatment with TCE. While the magnitude of induction of peroxisome proliferator-marker genes also declined, hepatocellular proliferation increased. This study offers a unique opportunity to provide a scientific data-driven rationale for some of the major assumptions in human health assessment of TCE.
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影响因子：
5.3
作者：
Lash, Lawrence H.;Chiu, Weihsueh A.;Guyton, Kathryn Z.;Rusyn, Ivan
通讯作者：
Rusyn, Ivan
影响因子：
10.4
作者：
Keshava N;Caldwell JC
通讯作者：
Caldwell JC
影响因子：
10.3
作者：
Hansen, Johnni;Sallmen, Markku;McLaughlin, Joseph K.
通讯作者：
McLaughlin, Joseph K.
影响因子：
3.8
作者：
Bradford, Blair U.;Lock, Eric F.;Rusyn, Ivan
通讯作者：
Rusyn, Ivan
影响因子：
3.8
作者：
Maloney, EK;Waxman, DJ
通讯作者：
Waxman, DJ