SITE-SELECTIVE DIFFERENCES IN CYTOCHROME-P450 ISOFORM ACTIVITIES - COMPARISON OF EXPRESSION IN RAT AND RHESUS-MONKEY LUNG AND INDUCTION IN RATS

The distribution of pulmonary cytochrome P450 (P450 or CYP) isoforms h as been investigated primarily in immunohistochemical studies, which a re neither quantitative nor reflective of the functions of these enzym es. 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 stu dy were to compare the activities of P450 monooxygenases in different lung subcompartments in two commonly studied animal models, be, rats a nd 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 (ethox yresorufin) and CYP2B (pentoxyresorufin) dealkylase activities were hi ghest in the parenchyma, whereas CYP2E1 (p-nitrophenol) hydroxylase ac tivity was highest in the airways. P450 reductase activities were simi lar in airways and parenchyma and were lower in trachea. In monkeys, n o significant site-selective differences in CYP1A1 and CYP2B1 activiti es were found. In contrast, CYP2E1 activity was higher in the distal b ronchioles and parenchyma than in the proximal airways, P450 reductase activities were similar in microsomes prepared from all subcompartmen ts of monkey lung. Induction of rat CYP1A1 activity by beta-naphthofla vone (administered ip) was much greater in the airways and lung parenc hyma (similar to 30-fold) than in the liver (similar to 10-fold) or tr achea (similar to 2.5-fold). Oral administration of phenobarbital or a cetone increased CYP2B and CYP2E1 activities in rat liver but had no s ignificant effect on P450 activities in subcompartments of rat lung. T hese findings support the conclusion that there are regiospecific and species-specific differences in the activities of P450 isoforms and th at the inducibility of rat pulmonary P450s is dependent on the isoform and lung region.