Comparison of Expression in Rat and Rhesus Monkey Lung and Induction in Rats
Abstract
The distribution of pulmonary cytochrome P450 (P450 or CYP) isoforms has been investigated primarily in immunohistochemical studies, which are neither quantitative nor reflective of the functions of these enzymes. Studies of enzyme activities have been performed using whole-lung homogenates or isolated cells, but there is little information on the regioselective expression of P450 monooxygenases. The aims of this study were to compare the activities of P450 monooxygenases in different lung subcompartments in two commonly studied animal models, i.e. rats and monkeys, and to explore the possibility that inducing agents would result in activity up-regulation that is highly site-selective, using rats as a model. Microdissection techniques were used to separate the airways from blood vessels and lung parenchyma. In rats, CYP1A1 (ethoxyresorufin) and CYP2B (pentoxyresorufin) dealkylase activities were highest in the parenchyma, whereas CYP2E1 (p-nitrophenol) hydroxylase activity was highest in the airways. P450 reductase activities were similar in airways and parenchyma and were lower in trachea. In monkeys, no significant site-selective differences in CYP1A1 and CYP2B1 activities were found. In contrast, CYP2E1 activity was higher in the distal bronchioles and parenchyma than in the proximal airways. P450 reductase activities were similar in microsomes prepared from all subcompartments of monkey lung. Induction of rat CYP1A1 activity by β-naphthoflavone (administered ip) was much greater in the airways and lung parenchyma (∼30-fold) than in the liver (∼10-fold) or trachea (∼2.5-fold). Oral administration of phenobarbital or acetone increased CYP2B and CYP2E1 activities in rat liver but had no significant effect on P450 activities in subcompartments of rat lung. These findings support the conclusion that there are regiospecific and species-specific differences in the activities of P450 isoforms and that the inducibility of rat pulmonary P450s is dependent on the isoform and lung region.
Footnotes
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Send reprint requests to: Kent E. Pinkerton, Ph.D., Institute of Toxicology and Environmental Health, University of California, Davis, CA 95616.
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This work was supported by National Institute of Environmental Health Sciences Grants ES04311, ES05707, ES00628, and RR00169 and California Tobacco-Related Disease Research Program Grants 4RT-0213 and 6RT-0327. The University of California, Davis, is a Center for Environmental Health Sciences.
- Abbreviation used is::
- P450 or CYP
- cytochrome P450
- Received August 29, 1997.
- Accepted January 2, 1998.
- The American Society for Pharmacology and Experimental Therapeutics
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