Mechanistic basis for nonlinearities and thresholds in rat liver carcinogenesis by the DNA-reactive carcinogens 2-acetylaminofluorene and diethylnitrosamine
Mechanistic basis for nonlinearities and thresholds in rat liver carcinogenesis by the DNA-reactive carcinogens 2-acetylaminofluorene and diethylnitrosamine
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DOI：
10.1177/019262330002800306
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发表时间：
2000-05-01
影响因子：
1.5
通讯作者：
Jeffrey, AM
中科院分区：
文献类型：
--
作者：
Williams, GM;Iatropoulos, MJ;Jeffrey, AM
探讨低暴露和高暴露致癌机制的差异。我们使用2种研究充分的DNA反应性致癌物2-乙酰氨基芴和二乙基亚硝胺，对大鼠肝癌发生进行了一系列暴露反应研究。在这些研究中，我们使用腹腔内注射或胃内滴注，以提供确切的剂量在一个起始段，然后苯巴比妥作为肝肿瘤促进剂，以提高表现的启动。该方案产生的致癌性与终生暴露于致癌物产生的致癌性相当。我们在这些实验中的发现提供了以下证据：（a）DNA加合物的形成可以是非线性的。在较高的暴露量下具有平台期：（B）细胞毒性显示无作用水平，并且与暴露量相关;（c）代偿性肝细胞增殖显示无作用水平，并且在高暴露量下可以是超线性的;（d）癌前肝细胞改变灶的形成可以显示无作用水平，并且在高暴露量下显示超线性的;（e）对于肿瘤发展可以存在无作用水平，并且暴露响应可以是超线性的。我们解释这些发现，以反映这些致癌物的肝细胞启动效应的阈值和夸大的反应，在高暴露归因于细胞毒性和代偿性肝细胞增殖。这种携带DNA损伤的肝细胞增殖的增强可能导致关键基因突变的过度产生，导致癌发生的超线性启动。因此，低暴露和高暴露的机制不同。基于这些观察。我们认为，从高毒性暴露的DNA反应性致癌物的假定低暴露效应的线性外推可能会产生高估。这种推断必须得到机械信息的支持。无作用水平的发现为理解为什么人类对DNA反应性致癌物的低水平环境暴露可能不会带来癌症风险提供了基础。
To explore differences in mechanisms of carcinogenicity at tow and high exposures. we have conducted a series of exposure response studies of hepatocarcinogenesis in rats using 2 well-studied DNA-reactive carcinogens, 2-acetylaminofluorene and diethylnitrasamine. In these studies, we have used intraperitoneal injection or intragastric instillation to deliver exact doses during an initiation segment followed by phenobarbital as a liver tumor promoter to enhance manifestation of initiation. This protocol results in carcinogenicity comparable to that produced by lifetime exposure to the carcinogens. Our findings in these experiments provide evidence for the following: (a) formation of DNA adducts can be nonlinear. with a plateau at higher exposures: (b) cytotoxicity shows no-effect Levels and is related to exposure; (c) compensatory hepatocyte proliferation shows no-effect levels and can be supralinear at high exposures: (d) formation of preneoplastic hepatocellular altered foci can show no-effect levels and appears supralinear at high exposures; (e) no-effect levels can exist for tumor development, and the exposure response can be supralinear. We interpret these findings to reflect thresholds for hepatocellular initiating effects of these carcinogens and exaggerated responses at high exposures attributable to cytotoxicity and compensatory hepatocyte proliferation. Such enhanced proliferation of hepatocytes harboring DNA damage likely results in an exaggerated yield of mutations in critical genes, Leading to supralinear initiation of carcinogenesis. Thus, mechanisms differ between low and high exposures. Based on these observations. we suggest that linear extrapolation from high toxic exposures to postulated low-exposure effects of DNA-reactive carcinogens can yield overestimates. Such extrapolation must be supported by mechanistic information. The finding of no-effect levels provides a basis for understanding why low-level environmental exposures of humans to even DNA-reactive carcinogens may convey no cancer risk.