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The Role of Metabolism in Chemical-Induced Pulmonary Toxicity*¹

Department of Drug Metabolism, Smithkline Beecham Pharmaceuticals, P.O. Box 1539, King of Prussia, Pennsylvania 19406

William R. Brian

Department of Drug Metabolism, Smithkline Beecham Pharmaceuticals, P.O. Box 1539, King of Prussia, Pennsylvania 19406

The lung is a target organ for the toxic effects of several chemical agents, including natural products, industrial chemicals, pesticides, environmental agents, and occasionally, drugs. Factors that establish the lung as a target organ include selective tissue exposure, high tissue oxygenation, and the presence of bioactivating systems that can generate toxic products from initially innocuous substances. Selective pulmonary exposure most often results from the fact that the lung serves as the major portal of entry for most airborne substances, but in some cases, selective exposure is the consequence of accumulation of agents, such as certain basic amines, from the circulation. Lung tumor development following long-term exposure to cigarette smoke or diesel engine exhaust is an example of pulmonary toxicity resulting from selective external exposure. Selective internal exposure, on the other hand, is exemplified by the pulmonary uptake of the herbicide paraquat from the circulation which is in part responsible for its lung-toxic effects. Although the lung contains drug metabolizing enzymes similar to those found in the liver, the enzymatic systems in the lung are sometimes highly concentrated in specific cell types. In the rabbit, for example, the lung-selective toxicity of the natural product ipomeanol is the consequence of relatively large amounts of cytochromes P450 2B1 and 4B1 in nonciliated bronchiolar epithelial cells (Clara cells) of the terminal airways. These P450 enzymes are highly proficient in vitro at converting ipomeanol to reactive products. Lung tissue contains other enzymic systems which are capable of catalyzing phase I biostransformation pathways (e.g., flavin-containing amine monooxygenase, amine oxidase, and prostaglandin synthase). Examples, however, where pulmonary metabolism by these pathways results in lung toxicity are less numerous than with P450 mediated reactions. Pulmonary prostaglandin H-synthase mediated cooxygenation has been shown to activate procarcinogens such as benzo(a)pyrene 7,8-dihydrodiol, aflatoxin B1, and monosubstituted hydrazines. The activities of pulmonary phase II (conjugation) pathways may also contribute to lung toxicity. Low glutathione transferase activity (relative to P450 mediated aryl hydrocarbon hydroxylase activity) in lung tissue has been suggested to correlate with elevated risk of lung cancer in smokers. Other examples of lung-specific toxic agents and possible causative roles of biotransformation are also discussed.

Key Words: Toxicity • cytochrome P450

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Toxicologic Pathology, Vol. 19, No. 4-1, 470-481 (1991)
DOI: 10.1177/019262339101900415


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This Article Abstract Free Full Text (Free PDF) Free Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Add to Saved Citations Download to citation manager Request Permissions Request Reprints Add to My Marked Citations Citing Articles Citing Articles via Google Scholar Citing Articles via Scopus Google Scholar Articles by Smith, B. R. Articles by Brian, W. R. Search for Related Content PubMed PubMed Citation Articles by Smith, B. R. Articles by Brian, W. R. Social Bookmarking                         What's this?