Previous chapters in this volume have delineated the complexity of the lung and the unique, selective responses of cells within the respiratory tract to xenobiotic exposure. In many cases lung-selective injury is simply related to the levels of toxicant reaching the respiratory tract. However, there are numerous, well-documented instances where selective exposure is not the underlying basis for target organ injury in the lung, and many of the agents that are capable of producing highly selective Clara cell or type II cell injury are discussed in later chapters of this volume. At the time of the publication of the first edition of Comprehensive Toxicology, there was a substantial body of information demonstrating the presence of several xenobiotic metabolizing enzymes in the respiratory tract that were capable of substrate metabolism, which consequently resulted in downstream toxicities. In the intervening 10 years since the publication, considerable new information demonstrating the presence of additional P450s in the lung and the association of single-nucleotide polymorphisms in these genes with the susceptibility of the lung to environmental toxicants has emerged. New information has been obtained that shows differences in specific activities of orthologous P450s in humans and animals, and while this has mainly been focused on hepatic drug metabolism, the introduction of humanized mice may yield better rodent models for assessing the long-term impacts of exposure to environmental and industrial chemicals that require biotransformation in the lung either as a clearance mechanism for substances that are biologically active or to activate chemicals that are inactive to biologically active derivatives. Generally, the high degree of localization of these proteins in cells of the respiratory tract is a key component of the susceptibility of the lung to certain metabolically activated toxicants, and metabolic activation of biologically inert chemicals remains the most likely role for these proteins in the lung. Thus, this chapter will enhance our understanding of the enzymes responsible for xenobiotic metabolism in the lung with special attention to species differences in metabolism that result in dramatic differences in the susceptibility of the respiratory tract to bioactivated toxicants. The ability to generate lung-selective, targeted deletions of cytochrome P450 reductase has been used to address directly the importance of pulmonary enzymes in the metabolic activation of tobacco-specific nitrosamines such as 4-(methylnitrosamine)-1-(3-pyridyl)-1-butanone (NNK). Such studies provide an important piece of evidence for the in situ metabolic activation of some substrates in the lung.
|Original language||English (US)|
|Title of host publication||Respiratory Toxicology|
|Number of pages||9|
|State||Published - Aug 12 2010|
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