Abstract
Studies in rodents have demonstrated the importance of cytochrome P450 monooxygenases in generating reactive metabolites that produce Clara cell injury. Pulmonary P450 activities in rodents are much higher than those in primates, raising the issue of relevance of rodent data to primates. Few studies on P450-catalyzed activation of cytotoxicants in subcompartments of primate lung have been reported. Accordingly, infant monkey airway subcompartments, including trachea, proximal, midlevel, distal airways, and parenchyma, were incubated with naphthalene or 1-nitronaphthalene to define metabolism at both high (500 μM) and low (50 μM) substrate concentrations. There was a relatively even distribution of metabolizing activities for naphthalene across subcompartments, but at high concentrations of 1-nitronaphthalene, lower airways (midlevel airway through parenchyma) showed higher bioactivation than upper airways. Dihydrodiol was the predominant water-soluble metabolite of naphthalene generated by all subcompartments, whereas covalently bound metabolites accounted for the greatest percentage of 1-nitronaphthalene metabolites, especially in lower airways. As anticipated, the amounts of metabolite covalently bound as a percentage of total metabolite formed increased dramatically with the 10-fold increase in substrate concentration. With both substrates, the formation of watersoluble metabolites was approximately 100 times less than observed previously in rodents. We conclude that 1) there are significant quantitative differences between rhesus and rodents in substrate bioactivation; 2) the distribution of metabolizing activities for naphthalene but not 1-nitronaphthalene is significantly different for rodents and primates; and 3) a very high percentage of the metabolites generated, particularly for 1-nitronaphthalene, is bound covalently to cellular proteins.
Footnotes
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This work was supported by National Institute of Environmental Health Sciences Grants ES08408, ES04311, ES04699, and ES00628. University of California Davis is a National Institute of Environmental Health Sciences Center in Environmental Health (ES05707), and support for core facilities used in this work is gratefully acknowledged. The California National Primate Research Center is supported by National Center for Research Resources RR00169.
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DOI: 10.1124/jpet.103.063669.
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ABBREVIATIONS: P450, cytochrome P450; HPLC, high-performance liquid chromatography; ANOVA, analysis of variance.
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↵1 These authors contributed equally to this work.
- Received February 23, 2004.
- Accepted April 12, 2004.
- The American Society for Pharmacology and Experimental Therapeutics
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