Kastelova A, Dimova S, Nemery B
Laboratory of Drug toxicology, Institute of Physiology, Bulgarian Academy of Sciences, Sofia, Bulgaria.
Methods Find Exp Clin Pharmacol. 2003 Dec;25(10):797-802. doi: 10.1358/mf.2003.25.10.793328.
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.
肺组织对诸如β-肾上腺素能拮抗剂等碱性药物（阳离子两亲性药物）的蓄积作用是众所周知的。在人和大鼠肝微粒体中，非选择性β-肾上腺素能阻滞剂普萘洛尔的环羟基化主要由细胞色素P450（CYP）2D6介导，而N-去异丙基化则由CYP1A2介导。在本研究中，由于反应性代谢产物（由4-羟基普萘洛尔形成）与肝微粒体P4502D酶的共价结合，普萘洛尔的重复给药导致肝脏代谢显著抑制，其全身可用性增加。肺中不存在CYP1A2而存在CYP2D，这表明普萘洛尔在肺中的代谢与在肝脏中的代谢不同。在本研究中，我们研究了其对大鼠II型肺细胞（RTII）和大鼠肺泡巨噬细胞（RAM）中一些外源性物质代谢酶的体内作用。在最后一次多次（7天）口服给药20小时后，普萘洛尔（100mg/kg体重）降低了RTII中NADPH细胞色素c还原酶活性以及7-苄氧基试卤灵（BROD）（CYP1A1、2A1、3A1）和7-乙氧基试卤灵（EROD）（CYP1A1）的细胞色素P-450依赖性脱烷基作用，而谷胱甘肽-S-转移酶（GST）、DT-黄递酶（QR）、γ-谷氨酰转移酶（γ-GT）活性、细胞内还原型谷胱甘肽水平以及7-戊氧基试卤灵（PROD）（CYP2B1）的脱烷基作用未发生变化。研究发现，普萘洛尔显著增加了RAM中的NADPH细胞色素c还原酶和BROD活性。结果表明，RTII和RAM对普萘洛尔的敏感性不同，且普萘洛尔对这两种细胞类型的肺外源性物质代谢酶活性具有相反的作用。
