LIVER-TUMOR INDUCTION IN B6C3F1 MICE BY DICHLOROACETATE AND TRICHLOROACETATE
LIVER-TUMOR INDUCTION IN B6C3F1 MICE BY DICHLOROACETATE AND TRICHLOROACETATE
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DOI：
10.1016/0300-483x(90)90195-m
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发表时间：
1990-09-01
期刊：
影响因子：
4.5
通讯作者：
LANSING, AJ
中科院分区：
文献类型：
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作者：
BULL, RJ;SANCHEZ, IM;LANSING, AJ
雄性和雌性B6 C3 F1小鼠在其饮用水中以1或2 g/l的浓度给予二氯乙酸盐（DCA）和三氯乙酸盐（TCA）长达52周。两种化合物在12个月内诱导雄性小鼠的肝增生性病变（HPL），包括肝细胞结节、腺瘤和肝细胞癌。TCA对HPL的诱导作用与剂量呈线性关系。与此相反，DCA的响应急剧增加的浓度从1到2 g/l的增加。37周时暂停DCA治疗导致52周时的HPL数量与根据给药总剂量预测的数量相同。然而，该治疗组中的病变均未进展为肝细胞癌。相反，当在37周时暂停TCA治疗时，在52周时的HPL产量显著低于通过给予的总剂量预测的产量。在该病例中，其余5处病变中有3处为肝细胞癌。在整个活性治疗期间，DCA治疗的小鼠显示出显著增大的肝脏，其特征在于显著的巨细胞和整个肝脏中肝细胞中糖原的大量积聚。在整个肝脏中观察到局灶性坏死区域。TCA产生细胞大小的小幅增加和更温和的糖原积累。TCA处理动物中未发生局灶性坏死损伤。TCA在肝脏中产生显著的脂褐素积累。DCA组脂褐素蓄积较低。这些数据证实了早期的观察结果，即DCA和TCA能够在B6 C3 F1小鼠中诱导肝肿瘤，并认为这两种相似化合物的肿瘤诱导机制存在显著差异。DCA的肿瘤发生可能在很大程度上依赖于继发于肝毒性损伤的细胞分裂刺激。另一方面，三氯乙酸似乎会增加脂质过氧化作用，这表明自由基的产生可能是其影响的原因。
Male and female B6C3F1 mice were administered dichloroacetate (DCA) and trichloroacetate (TCA) in their drinking water at concentrations of 1 or 2 g/l for up to 52 weeks. Both compounds induced hepatoproliferative lesions (HPL) in male mice, including hepatocellular nodules, adenomas and hepatocellular carcinomas within 12 months. The induction of HPL by TCA was linear with dose. In contrast, the response to DCA increased sharply with the increase in concentration from 1 to 2 g/l. Suspension of DCA treatment at 37 weeks resulted in the same number of HPL at 52 weeks that would have been predicted on the basis of the total dose administered. However, none of the lesions in this treatment group progressed to hepatocellar carcinomas. Conversely, the yield of HPL at 52 weeks when TCA treatment was suspended at 37 weeks was significantly below that which would have been predicted by the total dose administered. In this case, 3 of 5 remaining lesions were hepatocellular carcinomas. Throughout active treatment DCA-treated mice displayed greatly enlarged livers characterized by a marked cytomegaly and massive accumulation of glycogen in hepatocytes throughout the liver. Areas of focal necrosis were seen throughout the liver. TCA produced small increases in cell size and much a more modest accumulation of glycogen. Focal necrotic damage did not occur in TCA-treated animals. TCA produced marked accumulations of lipofuscin in the liver. Lipofuscin accumulation was less marked with DCA. These data confirm earlier observations that DCA and TCA are capable of inducing hepatic tumors in B6C3F1 mice and argue that the mechanisms in tumor induction differ substantially between these two similar compounds. Tumorigenesis by DCA may depend largely on stimulation of cell division secondary to hepatotoxic damage. On the other hand, TCA appears to increase lipid peroxidation, suggesting that production of radicals may be responsible for its effects.