RT Journal Article
SR Electronic
T1 Site-Selective Differences in Cytochrome P450 Isoform Activities
JF Drug Metabolism and Disposition
JO Drug Metab Dispos
FD American Society for Pharmacology and Experimental Therapeutics
SP 396
OP 400
VO 26
IS 5
A1 Chanhung Lee
A1 Katherine C. Watt
A1 Ai-Min Chang
A1 Charles G. Plopper
A1 Alan R. Buckpitt
A1 Kent E. Pinkerton
YR 1998
UL http://dmd.aspetjournals.org/content/26/5/396.abstract
AB 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. The American Society for Pharmacology and Experimental Therapeutics