Effects of heredity on response to drugs and environmental chemicals: construction of rodent models.
Effects of heredity on response to drugs and environmental chemicals: construction of rodent models.
复制标题
遗传对药物和环境化学品反应的影响：啮齿动物模型的构建。
DOI：
10.1021/tx960082y
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发表时间：
1996
期刊：
影响因子：
--
通讯作者：
Weber,WW
中科院分区：
文献类型：
--
作者：
Levy,GN;Rodgers,L;Weber,WW
随着生物学特别是遗传学中分子技术的出现，在药理学和毒理学研究中是否需要动物模型有时会受到质疑。虽然对遗传异质材料进行分子分析是可能的(尽管往往很困难)，但使用基因定义的样本简化了程序和对结果的解释。分离一个分子或对一个基因进行测序只是生物实验的开始；人们必须了解该序列在细胞、组织和全身中的功能和调节[1]。例如，我们可以克隆一种酶的基因，并将其导入细胞。这种酶催化测试化合物的激活，如果该化合物是致癌物质，可能会与DNA发生共价结合。这没有告诉我们致癌物质的目标组织，也没有关于免疫监测，这可能会在肿瘤形成之前消除突变细胞。然而，在一个完整的动物中，细胞和组织之间的所有生理相互作用都存在，并且可以真正确定毒性或致癌性。人们选择人类对药物或致癌物反应的动物模型，认为这将有助于剖析人类反应的遗传基础，识别导致反应的生化和药理学机制，并帮助评估反应的生物学意义。被证明是评估新药疗法的糟糕模型的动物模型，在阐明涉及人类疾病的途径的分子和药理学基础方面可能仍然是很好的。在动物身上建模的过程包括在模型和人类之间来回切换，尽可能地在两个系统之间比较结果。在人类中，一般情况下接触外源物质，特别是致癌物质，是很难测量的。虽然治疗性药物可能是一个例外，但大多数环境异生物质都是在单独可变的剂量下遇到的。遗传因素、年龄、性别和其他操作因素可以极大地影响遇到的化合物的药代动力学和药效学。这些因素对人类对药物或致癌物反应的影响通常可以通过系谱分析、基因分离和药理学或毒理学反应的结构分析来检验。然而，在动物中，这些有限的方法可以通过菌株调查、测试杂交、对重组和同源菌株的研究以及基因靶向来补充。在动物身上进行的研究在人类是不可能的，可以揭示哪些细胞类型参与了感兴趣化合物的代谢，代谢途径的关键酶是什么，哪些基因负责相关酶的合成，这些基因及其产物是如何控制的，以及是否有
With the emergence of molecular techniques in biology and in genetics in particular, the need for animal models in studies of pharmacology and toxicology is sometimes questioned. While it is possible (although often difficult) to do molecular analysis on genetically heterogeneous material, the use of genetically defined samples simplifies the procedures and the interpretation of the results. Isolating a molecule or sequencing a gene is only the beginning of a biological experiment; one must learn the function and regulation of the sequence in cell, tissue, and whole body (1). For example, we can clone the gene for an enzyme and transfect it into a cell. The enzyme catalyzes activation of a test compound, and perhaps, if the compound is a carcinogen, covalent binding to DNA occurs. This tells us nothing about the target tissue for the carcinogen and nothing about immune surveillance which may eliminate the mutated cell before tumor formation ever occurs. In an intact animal, however, all the physiological interactions between cells and tissues are present and the true determination of toxicity or carcinogenicity can be made. One chooses an animal model of the human response to a drug or carcinogen with the idea that it will contribute to the dissection of the genetic basis of the human response, to identify the biochemical and pharmacological mechanism responsible for the response, and to help in assessing the biological significance of the response. Animal models that turn out to be poor models for assessing a new drug therapy may still be excellent for elucidating the molecular and pharmacological basis of pathways involved in human disease. The process of modeling in animals involves going back and forth between the model and humans, comparing results between the two systems whenever possible.In humans, exposure to xenobiotics in general and to carcinogens in particular is difficult to measure. While therapeutic pharmaceuticals are a possible exception, most environmental xenobiotics are encountered at individually variable dosages. Genetic factors, age, sex, and other operant factors can greatly affect the pharmacokinetics and pharmacodynamics of an encountered compound. The influence of these factors on human response to a drug or carcinogen can often be examined by pedigree analysis, gene isolation, and structural analysis of the pharmacological or toxicological response. In animals, however, these limited methods can be supplemented by strain surveys, test crosses, studies in recombinant and congenic strains, and gene targeting. Studies in animals which are impossible in humans can reveal which cell types are involved in metabolism of the compound of interest, what are the key enzymes of the metabolic pathway, what genes are responsible for synthesis of the relevant enzymes, how these genes and their products are controlled, and whether there are