THE ROLE OF DICHLOROACETATE IN THE HEPATOCARCINOGENICITY OF TRICHLOROETHYLENE
THE ROLE OF DICHLOROACETATE IN THE HEPATOCARCINOGENICITY OF TRICHLOROETHYLENE
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DOI：
10.1016/0378-4274(93)90131-g
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发表时间：
1993-05-01
影响因子：
3.5
通讯作者：
STEVENS, DK
中科院分区：
文献类型：
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作者：
BULL, RJ;TEMPLIN, M;STEVENS, DK
经三氯乙烯（TRI）处理的B6C3F1小鼠肝脏肿瘤的诱导归因于其对三氯乙酸（TCA）的代谢。在小鼠体内，三氯乙酸是一种有效的过氧化物酶体增殖剂，其血液浓度很容易达到致癌剂量的TRI。最近的数据表明，TCA和二氯乙酸（DCA）都能诱导B6C3F1小鼠的肝脏肿瘤。虽然DCA被认为是TRI的代谢物，但很少有人关注DCA在TRI的肝癌作用中可能发挥的作用。DCA和TCA对B6C3F1小鼠肝脏的影响有显著差异。三氯乙酸处理诱导过氧化物酶体增殖，增加脂质沉积，并导致肝脏中脂褐素的显著积累。二氯乙酸引起肝脏显著增大，伴有巨细胞病和糖原大量积聚。巨细胞病与复发性肝坏死的病灶区域的发展有关，这反过来又导致这些病变周围区域的高水平细胞增殖。DCA诱导过氧化物酶体是短暂的，脂褐素的积累比TCA治疗明显得多。对TRI代谢的研究表明，血液中产生的DCA水平足以解释TRI的肝致癌作用。与TCA浓度相比，在接受TRI治疗的小鼠尿液中发现的DCA浓度相当低，这是由于DCA的代谢更加迅速和完全。这些数据并不支持TRI的肝癌作用仅仅与过氧化物酶体增殖有关的结论。
The induction of hepatic tumors in B6C3F1 mice treated with trichloroethylene (TRI) has been attributed to its metabolism to trichloroacetate (TCA). Trichloroacetate is an effective peroxisome proliferator in mice at blood concentrations that are readily achieved with carcinogenic doses of TRI. Recent data has demonstrated that both TCA and dichloroacetate (DCA) are capable of inducing liver tumors in B6C3F1 mice. Although long recognized as a metabolite of TRI, little attention has focussed on the role DCA might play in the hepatocarcinogenic effects of TRI. There are significant differences in the effects of DCA and TCA on the liver of B6C3F1 mice. Trichloroacetate treatment induces peroxisome proliferation, increases lipid deposition, and results in a marked accumulation of lipofuscin in the liver with long-term exposures. Dichloroacetate induces a markedly enlarged liver associated with a cytomegaly and large accumulations of glycogen. The cytomegaly is associated with the development of focal areas of recurrent liver necrosis which in tum lead to high levels of cell proliferation in the area surrounding these lesions. Induction of peroxisomes with DCA is transitory and the accumulation of lipofuscin is much less evident than with TCA treatment. Studies of TRI metabolism demonstrate that blood levels of DCA produced are sufficient to account for the hepatocarcinogenic effects of TRI. The rather low concentrations of DCA found in the urine of mice treated with TRI relative to TCA concentrations are due to the much more rapid and complete metabolism of DCA. These data do not support the conclusion that the hepatocarcinogenic effects of TRI are simply related to peroxisome proliferation.