Environmental and chemical carcinogenesis
Environmental and chemical carcinogenesis
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DOI：
10.1016/j.semcancer.2004.06.010
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发表时间：
2004-12-01
影响因子：
14.5
通讯作者：
Loeb, LA
中科院分区：
文献类型：
--
作者：
Wogan, GN;Hecht, SS;Loeb, LA
人们不断地暴露在外源的不同数量的化学物质中，这些化学物质在实验系统中已被证明具有致癌或致突变特性。当这些物质存在于食物、空气或水中时，暴露可能是外源性的，当它们是代谢或病理生理状态（如炎症）的产物时，暴露也可能是内源性的。据估计，如果接触环境化学致癌物与饮食、烟草使用等“生活方式”因素有关，则接触环境化学致癌物可能对相当一部分，也许是大多数人类癌症的病因起着重要作用。本章总结了已被广泛研究的环境化学致癌的几个方面，并说明了机制调查结合分子流行病学方法在建立环境暴露与癌症风险增加之间的因果关系方面的力量。黄曲霉毒素是亚洲和非洲饮食中的一种强致癌性霉菌产生的污染物，其暴露与原发性肝癌风险升高之间的因果关系已通过分子流行病学中经过充分验证的生物标志物的应用得到证实。这些研究还发现，黄曲霉毒素和乙型肝炎病毒感染在增加肝癌风险方面具有显著的协同作用。烟草制品的使用提供了一个由涉及致癌物接触的生活方式因素引起癌症的明确例子。烟草致癌物及其DNA加合物是烟草制品诱发癌症的核心，特定烟草致癌物（如多环芳烃和NNK）对烟草诱发肺癌的贡献可通过证据权重法进行评估。考虑的因素包括烟草制品中的存在、实验动物的致癌性、人的摄取、代谢和加合物的形成、在引起致癌基因或抑制基因分子变化中的可能作用，以及其他相关数据。这种方法可以应用于其他环境致癌物的评估，并且结合表型致癌物特异性生物标志物的前瞻性流行病学研究将显著促进评估。杂环胺是一类重要的食品致癌物。它们是实验动物体内许多器官部位的诱变剂和致癌物，是肉类在180度以上长期加热时产生的。其中四种化合物可以在北美饮食中的熟透肉制品中持续检测到，尽管因果关系尚未确定，但大多数流行病学研究已将食用熟透肉制品与结肠癌、乳腺癌和胃癌联系起来。采用分子生物标志物的研究表明，个体对这些致癌物的易感性可能存在差异，遗传多态性可能导致这种差异。与大多数其他化学致癌物一样，杂环胺本身并不致癌，但在与DNA反应之前，必须由细胞色素P450酶家族代谢为化学反应性亲电试剂，从而引发致癌反应。这些相同的细胞色素P450酶，以及作用于细胞色素P450代谢产物的酶（如葡萄糖醛基转移酶、谷胱甘肽s-转移酶等），也通过失活途径代谢化学物质，而激活和解毒的相对数量将决定一种化学物质是否致癌。因为遗传和环境因素都会影响代谢激活和解毒化学物质的酶的水平，它们也会影响致癌风险。癌细胞的许多表型可能是突变的结果，即随着肿瘤进展而积累的DNA核苷酸序列的变化。这些可能由于DNA损伤或在DNA合成过程中非互补核苷酸的掺入而产生。基于在人类肿瘤中罕见的自发突变和大量突变之间的差异，人们假设癌症必须表现出突变表型，这将代表癌症进展的早期事件。突变表型可以由通常保证遗传稳定性的基因突变产生。这些突变可能是由环境或内源性因子引起的DNA损伤引起的，但突变表型的获得是否是肿瘤进展过程中的必要事件仍有待确定。(C) 2004 Elsevier Ltd.版权所有。
People are continuously exposed exogenously to varying amounts of chemicals that have been shown to have carcinogenic or mutagenic properties in experimental systems. Exposure can occur exogenously when these agents are present in food, air or water, and also endogenously when they are products of metabolism or pathophysiologic states such as inflammation. It has been estimated that exposure to environmental chemical carcinogens may contribute significantly to the causation of a sizable fraction, perhaps a majority, of human cancers, when exposures are related to "life-style" factors such as diet, tobacco use, etc. This chapter summarizes several aspects of environmental chemical carcinogenesis that have been extensively studied and illustrates the power of mechanistic investigation combined with molecular epidemiologic approaches in establishing causative linkages between environmental exposures and increased cancer risks.A causative relationship between exposure to aflatoxin, a strongly carcinogenic mold-produced contaminant of dietary staples in Asia and Africa, and elevated risk for primary liver cancer has been demonstrated through the application of well-validated biomarkers in molecular epidemiology. These studies have also identified a striking synergistic interaction between aflatoxin and hepatitis B virus infection in elevating liver cancer risk. Use of tobacco products provides a clear example of cancer causation by a life-style factor involving carcinogen exposure. Tobacco carcinogens and their DNA adducts are central to cancer induction by tobacco products, and the contribution of specific tobacco carcinogens (e.g. PAH and NNK) to tobacco-induced lung cancer, can be evaluated by a weight of evidence approach. Factors considered include presence in tobacco products, carcinogenicity in laboratory animals, human uptake, metabolism and adduct formation, possible role in causing molecular changes in oncogenes or suppressor genes, and other relevant data. This approach can be applied to evaluation of other environmental carcinogens, and the evaluations would be markedly facilitated by prospective epidemiologic studies incorporating phenotypic carcinogen-specific biomarkers.Heterocyclic amines represent an important class of carcinogens in foods. They are mutagens and carcinogens at numerous organ sites in experimental animals, are produced when meats are heated above 180 degreesC for long periods. Four of these compounds can consistently be identified in well-done meat products from the North American diet, and although a causal linkage has not been established, a majority of epidemiology studies have linked consumption of well-done meat products to cancer of the colon, breast and stomach. Studies employing molecular biomarkers suggest that individuals may differ in their susceptibility to these carcinogens, and genetic polymorphisms may contribute to this variability. Heterocyclic amines, like most other chemical carcinogens, are not carcinogenic per se but must be metabolized by a family of cytochrome P450 enzymes to chemically reactive electrophiles prior to reacting with DNA to initiate a carcinogenic response. These same cytochrome P450 enzymes-as well as enzymes that act on the metabolic products of the cytochromes P450 (e.g. glucuronyl transferase, glutathione S-transferase and others)-also metabolize chemicals by inactivation pathways, and the relative amounts of activation and detoxification will determine whether a chemical is carcinogenic. Because both genetic and environmental factors influence the levels of enzymes that metabolically activate and detoxify chemicals, they can also influence carcinogenic risk.Many of the phenotypes of cancer cells can be the result of mutations, i.e., changes in the nucleotide sequence of DNA that accumulate as tumors progress. These can arise as a result of DNA damage or by the incorporation of non-complementary nucleotides during DNA synthetic processes. Based upon the disparity between the infrequency of spontaneous mutations and the large numbers of mutations reported in human tumors, it has been postulated that cancers must exhibit a mutator phenotype, which would represent an early event in cancer progression. A mutator phenotype could be generated by mutations in genes that normally function to guarantee genetic stability. These mutations presumably arise via DNA damage by environmental or endogenous agents, but it remains to be determined whether the acquisition of a mutator phenotype is a necessary event during tumor progression. (C) 2004 Elsevier Ltd. All rights reserved.