Mode of action of liver tumor induction by trichloroethylene and its metabolites, trichloroacetate and dichloroacetate.
Mode of action of liver tumor induction by trichloroethylene and its metabolites, trichloroacetate and dichloroacetate.
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DOI：
10.1289/ehp.00108s2241
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发表时间：
2000-05
影响因子：
10.4
通讯作者：
Bull RJ
中科院分区：
文献类型：
--
作者：
Bull RJ
三氯乙烯（TCE）在小鼠中诱发肝癌，但在大鼠中不诱发肝癌。三氯乙烯的三种代谢产物可能起作用-水合氯醛（CH）、二氯乙酸酯（DCA）和三氯乙酸酯（TCA）。CH和TCA似乎只能在小鼠中诱导肝肿瘤，但DCA在大鼠中也有活性。诱发肝癌所需的血液中TCA浓度接近mM范围。血液中与致癌作用相关的DCA浓度在亚微米范围内。CH的致癌活性在很大程度上取决于其转化为TCA和/或DCA。TCA是一种过氧化物酶体增殖剂，其剂量范围与诱发肝癌相同。具有过氧化物酶体增殖物激活受体α（PPAR-alpha）靶向破坏的小鼠对其他过氧化物酶体增殖物的肝癌诱导特性不敏感。人类细胞不显示在啮齿动物中观察到的与PPAR-alpha相关的反应。这可能归因于人肝脏中表达的PPAR-alpha水平较低。DCA治疗产生的肝肿瘤具有与TCA不同的表型。它的致瘤作用与对肿瘤、正常肝细胞中细胞复制率的不同作用以及对细胞凋亡的抑制密切相关。DCA诱导的肿瘤的生长已被证明在停止治疗后停止。DCA和TCA充分解释了TCE的致癌反应。低水平接触三氯乙烯不太可能诱发人类肝癌。较高的三氯乙烯暴露量可能会影响敏感人群。敏感性可能基于TCE或其代谢物的不同代谢能力，或由具有遗传基础的某些慢性疾病引起。
Trichloroethylene (TCE) induces liver cancer in mice but not in rats. Three metabolites of TCE may contribute--chloral hydrate (CH), dichloroacetate (DCA), and trichloroacetate (TCA). CH and TCA appear capable of only inducing liver tumors in mice, but DCA is active in rats as well. The concentrations of TCA in blood required to induce liver cancer approach the mM range. Concentrations of DCA in blood associated with carcinogenesis are in the sub-microM range. The carcinogenic activity of CH is largely dependent on its conversion to TCA and/or DCA. TCA is a peroxisome proliferator in the same dose range that induces liver cancer. Mice with targeted disruptions of the peroxisome proliferator-activated receptor alpha (PPAR-alpha) are insensitive to the liver cancer-inducing properties of other peroxisome proliferators. Human cells do not display the responses associated with PPAR-alpha that are observed in rodents. This may be attributed to lower levels of expressed PPAR-alpha in human liver. DCA treatment produces liver tumors with a different phenotype than TCA. Its tumorigenic effects are closely associated with differential effects on cell replication rates in tumors, normal hepatocytes, and suppression of apoptosis. Growth of DCA-induced tumors has been shown to arrest after cessation of treatment. The DCA and TCA adequately account for the hepatocarcinogenic responses to TCE. Low-level exposure to TCE is not likely to induce liver cancer in humans. Higher exposures to TCE could affect sensitive populations. Sensitivity could be based on different metabolic capacities for TCE or its metabolites or result from certain chronic diseases that have a genetic basis.
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影响因子：
5.1
作者：
BIGNAMI, M;CONTI, G;CARERE, A
通讯作者：
CARERE, A
影响因子：
4.5
作者：
BULL, RJ;SANCHEZ, IM;LANSING, AJ
通讯作者：
LANSING, AJ
影响因子：
3.5
作者：
BULL, RJ;TEMPLIN, M;STEVENS, DK
通讯作者：
STEVENS, DK
影响因子：
3.4
作者：
ABELSON, PH
通讯作者：
ABELSON, PH
影响因子：
3.5
作者：
Carter, JH;Carter, HW;DeAngelo, AB
通讯作者：
DeAngelo, AB