Williams G M, Iatropoulos M J, Weisburger J H
American Health Foundation, Valhalla, NY 10595, USA.
Exp Toxicol Pathol. 1996 Feb;48(2-3):101-11. doi: 10.1016/S0940-2993(96)80030-3.
Chemical carcinogens are of two distinct types, DNA-reactive and epigenetic. Testing methodology can be directed toward detecting effects of both types of carcinogen. Carcinogens of the DNA-reactive type are defined by the formation of covalently bound DNA adducts. These chemicals have structures that yield electrophilic reactants either directly or after bioactivation. These agents cause genomic alteration in the structure or function of DNA in the target cell. In addition, these compounds can exert other cellular and tissue epigenetic effects, such as cell proliferation and growth promotion. Carcinogens of the epigenetic (paragenetic) type, in contrast, do not react with DNA, but rather display cellular effects such as neoplasm growth promotion, cytotoxicity, inhibition of tissue growth regulation, peroxisome proliferation, endocrine modification, immunosuppression and/or sustained tissue ischemia that can be the basis for increases in neoplasia. Their chemical structure is such that they do not give rise to a reactive electrophile. The testing methodologies to identify either type follow a Decision Point Approach designed to identify potential carcinogenicity and yield mechanistic information on the production of effects that underlie carcinogenicity. It has 5 stages focusing on the chemical structure, DNA-reactivity, epigenetic effects, limited bioassays and finally the application of the accelerated bioassay (ABA). ABA requires 40 weeks and applies the use of sensitive markers for induction of neoplasia in comparison to positive control compounds for important organs in human carcinogenesis. It enables data acquisition of the entire carcinogenic process directed toward developing mechanistic information. The ABA has the potential to replace the chronic bioassay in rodents in some circumstances and can serve as an alternative to a chronic bioassay in a second species.
化学致癌物有两种不同类型，即DNA反应性致癌物和表观遗传致癌物。检测方法可以针对检测这两种类型致癌物的作用。DNA反应性致癌物是通过共价结合的DNA加合物的形成来定义的。这些化学物质具有直接或在生物活化后产生亲电反应物的结构。这些物质会导致靶细胞中DNA的结构或功能发生基因组改变。此外，这些化合物还可以产生其他细胞和组织的表观遗传效应，如细胞增殖和生长促进。相比之下，表观遗传（旁遗传）类型的致癌物不与DNA反应，而是表现出诸如肿瘤生长促进、细胞毒性、组织生长调节抑制、过氧化物酶体增殖、内分泌改变、免疫抑制和/或持续性组织缺血等细胞效应，这些效应可能是肿瘤形成增加的基础。它们的化学结构使其不会产生反应性亲电试剂。识别这两种类型致癌物的检测方法遵循一种决策点方法，旨在识别潜在致癌性并提供有关致癌作用基础的效应产生的机制信息。它有5个阶段，重点关注化学结构、DNA反应性、表观遗传效应、有限的生物测定，最后是加速生物测定（ABA）的应用。ABA需要40周时间，与人类致癌过程中重要器官的阳性对照化合物相比，使用敏感标记物来诱导肿瘤形成。它能够获取整个致癌过程的数据，以建立机制信息。在某些情况下，ABA有可能取代啮齿动物的慢性生物测定，并可作为第二种物种慢性生物测定的替代方法。
