Boyd M R, Grygiel J J, Minchin R F
Clin Exp Pharmacol Physiol. 1983 Jan-Feb;10(1):87-99. doi: 10.1111/j.1440-1681.1983.tb00175.x.
Historically, the concept of metabolic activation was first forwarded to explain the in vivo activity of certain carcinogenic chemicals that without prior metabolism were chemically inert and biologically inactive. Subsequently, the concept has been extended to explain the effects of many different classes of chemicals causing diverse toxicities. Because of its major role in drug metabolism, the liver is a prominent site for toxic injury by agents requiring metabolic activation. The liver can also be the source of reactive metabolites that damage extrahepatic organs. But, organ selective toxicity can also result from the in situ metabolic activation of foreign chemicals in extrahepatic target tissues such as the lungs and the kidneys. Moreover, extrahepatic tissues generally are much more heterogeneous in cellular composition compared to the liver, and the localization of drug metabolizing enzymes in certain cell populations may result in highly cell selective toxic injury. The significance of metabolic activation and toxicity--and the importance of the particular chemical structure of individual compounds, as well as host factors such as species, age, sex, and pretreatment effects--on target-organ-selective toxicity by reactive metabolites are illustrated by studies with various furan derivatives, an important class of environmental chemicals.
从历史角度来看，代谢活化的概念最初是为了解释某些致癌化学物质在体内的活性而提出的，这些化学物质在未经代谢之前是化学惰性且生物无活性的。随后，这一概念被扩展，用于解释许多不同种类化学物质产生各种毒性的作用机制。由于肝脏在药物代谢中起主要作用，它是需要代谢活化的药物导致毒性损伤的主要部位。肝脏也可能是产生损伤肝外器官的反应性代谢物的来源。但是，器官选择性毒性也可能源于肝外靶组织（如肺和肾）中异物化学物质的原位代谢活化。此外，与肝脏相比，肝外组织在细胞组成上通常更加多样化，药物代谢酶在某些细胞群体中的定位可能导致高度细胞选择性的毒性损伤。各种呋喃衍生物（一类重要的环境化学物质）的研究表明了代谢活化和毒性的重要性，以及单个化合物的特定化学结构以及宿主因素（如物种、年龄、性别和预处理效应）对反应性代谢物引起的靶器官选择性毒性的重要性。
