Chloroform, carbon tetrachloride and glutathione depletion induce secondary genotoxicity in liver cells via oxidative stress
Chloroform, carbon tetrachloride and glutathione depletion induce secondary genotoxicity in liver cells via oxidative stress
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DOI：
10.1016/s0300-483x(03)00058-1
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发表时间：
2003-05-03
期刊：
影响因子：
4.5
通讯作者：
Chipman, JK
中科院分区：
文献类型：
--
作者：
Beddowes, EJ;Faux, SP;Chipman, JK
化学致癌物一般分为遗传毒性和非遗传毒性。然而，有时在高浓度下观察到微弱的遗传毒性，并且解释通常是有问题的。此外，某些啮齿动物致癌物在与细胞毒性相关的剂量下发挥作用，代偿性增生可能是肿瘤发生的一个促成因素。我们假设，某些物质在高浓度下可通过谷胱甘肽（GSH）和其他抗氧化防御的消耗诱导氧化应激，这可能导致间接遗传毒性，从而导致致癌性。为了支持这一点，在与脂质过氧化相关的条件下，用丁硫基乙磺酰亚胺（BSO）处理以耗尽GSH的人HepG 2细胞显示出DNA链断裂以及升高的8-氧代脱氧鸟苷（8-oxodG）和丙二醛脱氧鸟苷（M（1）dG）加合物。氯仿和四氯化碳是啮齿动物致癌物，具有上述特征。在雌性大鼠肝细胞中，氯仿处理导致M（1）dG加合物（4 mM及以上）、DNA链断裂（8 mM及以上）和脂质过氧化的少量剂量依赖性增加，而DNA氧化没有任何相关增加。GSH消耗仅与细胞毒性相关（20 mM;乳酸脱氢酶释放）。除了脂质过氧化，四氯化碳（I和4毫米）产生了一个小的海拔在M I dG加合物和DNA链断裂和增加8-oxodG观察到的阈值，并伴随着，细胞毒性（4毫米）。这些影响可能导致高剂量遗传毒性和致癌性。基于抗氧化剂的消耗，预期剂量反应的非线性，因此，应存在生物学相关反应的实用阈值。(C)2003爱思唯尔科学爱尔兰有限公司保留所有权利。
Chemical carcinogens are generally classified, as genotoxic or non-genotoxic. However, weak genotoxicity at high concentrations is sometimes observed and interpretation is often problematic. In addition, certain rodent carcinogens exert their effects at doses associated with cytotoxicity and compensatory hyperplasia may be a contributing factor to tumourogenesis. We hypothesise that certain substances, at high concentrations, can induce an oxidative stress via the depletion of glutathione (GSH) and other antioxidant defences and that this may lead to indirect genotoxicity, that could contribute to carcinogenicity. In support of this, human HepG2 cells treated with buthionine sulphoximine (BSO) to deplete GSH, exhibited DNA strand breaks alongside elevated 8-oxodeoxyguanosine (8-oxodG) and malondialdehyde deoxyguanosine (M(1)dG) adducts under conditions associated with lipid peroxidation. Chloroform and carbon tetrachloride are rodent carcinogens with characteristics as described above. In female rat hepatocytes, chloroform treatment resulted in a small dose-dependent increase in M(1)dG adducts (4 mM and above), DNA strand breakage (8 mM and above) and lipid peroxidation, in the absence of any associated increase in DNA oxidation. GSH depletion only occurred in association with cytotoxicity (20 mM; lactate dehydrogenase release). Alongside lipid peroxidation, carbon tetrachloride (I and 4 mM) produced a small elevation in M I dG adducts and DNA strand breaks and increases in 8-oxodG were observed at the threshold of, and concomitant with, cytotoxicity (4 mM). These effects may contribute to high dose genotoxicity and carcinogenicity. Non-linearity in the dose response is expected on the basis of depletion of antioxidants, and therefore, a pragmatic threshold for biologically relevant responses should exist. (C) 2003 Elsevier Science Ireland Ltd. All rights reserved.