Effects of propranolol on xenobiotic enzyme activities in rat type II pneumocytes and alveolar macrophages in vivo.

Abstract

The accumulation of basic drugs (cationic amphiphilic), such as beta-adrenergic antagonists, by pulmonary tissue is well known. Ring hydroxylation of nonselective beta-adrenergic blocking agent propranolol is mediated mainly by cytochrome P450 (CYP) 2D6 and N-desisopropylation by CYP1A2 in human and rat liver microsomes. In this study, the repeated administration of propranolol resulted in a marked inhibition of hepatic metabolism and an increase in its systemic availability, due to covalent binding of reactive metabolites (formed from 4-OH-propranolol) to liver microsomal P4502D enzymes. The absence of CYP1A2 and the presence of CYP2D in the lung suggest a different pulmonary metabolism of propranolol in comparison with those in the liver. In this study, we investigated its effects in vivo on some xenobiotic-metabolizing enzymes in rat type II pneumocytes (RTII) and rat alveolar macrophages (RAM). Twenty hours after the last multiple (7 days) oral administration, propranolol (100 mg/kg b.w.) decreased NADPH cytochrome c reductase activity and cytochrome P-450-dependent dealkylation of 7-benzyloxyresorufin (BROD) (CYP1A1, 2A1, 3A1) and 7-ethoxyresorufin (EROD) (CYP1A1) in RTII, while glutathione-S-transferase (GST), DT-diaphorase (QR), gamma-glutamyl transferase (gamma-GT) activities, intracellular reduced glutathione level and dealkylation of 7-pentoxyresorufin (PROD) (CYP2B1) were not changed. It was found that propranolol significantly increased NADPH cytochrome c reductase and BROD activities in RAM. The results suggest a different susceptibility of RTII and RAM to propranolol and its contrary effects on lung xenobiotic-metabolizing enzyme activities in both types of cells.