Buckpitt A, Boland B, Isbell M, Morin D, Shultz M, Baldwin R, Chan K, Karlsson A, Lin C, Taff A, West J, Fanucchi M, Van Winkle L, Plopper C
Department of Molecular Biosciences, School of Veterinary Medicine, University of California, Davis, CA 95616, USA.
Drug Metab Rev. 2002 Nov;34(4):791-820. doi: 10.1081/dmr-120015694.
The lung, which is in intimate contact with the external environment, is exposed to a number of toxicants both by virtue of its large surface area and because it receives 100% of the cardiac output. Lung diseases are a major disease entity in the U.S. population ranking third in terms of morbidity and mortality. Despite the importance of these diseases, key issues remain to be resolved regarding the interactions of chemicals with lung tissue and the factors that are critical determinants of chemical-induced lung injury. The importance of cytochrome P450 monooxygenase dependent metabolism in chemical-induced lung injury in animal models was established over 25 years ago with the furan, 4-ipomeanol. Since then, the significance of biotransformation and the reasons for the high degree of pulmonary selectivity for a myriad of different chemicals has been well documented, mainly in rodent models. However, with many of these chemicals there are substantial differences in the susceptibility of rats vs. mice. Even within the same species, varied levels of the respiratory tract respond differently. Thus, key pieces of data are still missing when evaluating the applicability of data generated in rodents to primates, and as a result of this, there are substantial uncertainties within the regulatory community with regards to assessing the risks to humans for exposure to some of these chemicals. For example, all of the available data suggest that the levels of cytochrome P450 monooxygenases in rodent lungs are 10-100 times greater than those measured in the lungs of nonhuman primates or in man. At first glance, this suggests that a significant margin of safety exists when evaluating the applicability of rodent studies in the human, but the issues are more complex. The intent of this review is to outline some of the work conducted on the site and species selective toxicity and metabolism of the volatile lung toxic aromatic hydrocarbon, naphthalene. We argue that a complete understanding of the cellular and biochemical mechanisms by which this and other lung toxic compounds generate their effects in rodent models with subsequent measurement of these cellular and biochemical events in primate and human tissues in vitro will provide a far better basis for judging whether the results of studies done in rodent models are applicable to humans.
肺与外部环境密切接触，因其表面积大且接受100%的心输出量，所以会接触到多种有毒物质。肺部疾病是美国人群中的主要疾病类型，在发病率和死亡率方面排名第三。尽管这些疾病很重要，但关于化学物质与肺组织的相互作用以及化学物质诱导肺损伤的关键决定因素等关键问题仍有待解决。25多年前，通过呋喃、4-异戊二烯醇在动物模型中证实了细胞色素P450单加氧酶依赖性代谢在化学物质诱导肺损伤中的重要性。从那时起，生物转化的重要性以及多种不同化学物质对肺具有高度选择性的原因已得到充分记录，主要是在啮齿动物模型中。然而，对于许多这些化学物质，大鼠和小鼠的易感性存在很大差异。即使在同一物种内，呼吸道的不同水平反应也不同。因此，在评估啮齿动物产生的数据对灵长类动物的适用性时，关键数据仍然缺失，因此，监管机构在评估人类接触某些这些化学物质的风险方面存在很大的不确定性。例如，所有现有数据表明，啮齿动物肺部的细胞色素P450单加氧酶水平比在非人类灵长类动物或人类肺部测得的水平高10至100倍。乍一看，这表明在评估啮齿动物研究对人类的适用性时存在显著的安全边际，但问题更为复杂。本综述的目的是概述关于挥发性肺毒性芳香烃萘的部位和物种选择性毒性及代谢所开展的一些工作。我们认为，全面了解该物质和其他肺毒性化合物在啮齿动物模型中产生作用的细胞和生化机制，随后在体外灵长类动物和人类组织中测量这些细胞和生化事件，将为判断啮齿动物模型研究结果是否适用于人类提供更好的依据。
