Sinal C J, Zhu L F, Zhong R, Cherian M G, Bend J R
Department of Pharmacology and Toxicology, University of Western Ontario, London, Canada.
Can J Physiol Pharmacol. 1995 Jan;73(1):146-52. doi: 10.1139/y95-022.
Although liver transplantation has been the subject of intensive investigation, comparatively little is known regarding the effects of this procedure on the metabolism of xenobiotics. The objective of the present study was to examine the effect of orthotopic liver transplantation on rat hepatic, pulmonary, and renal microsomal cytochrome P450 (P450) monooxygenase activity through the use of isozyme-selective substrates. Pulmonary microsomal P450 1A1 dependent 7-ethoxyresorufin O-deethylation (ERFD) activity increased over time in recipient rats, with maximal induction (750% of donor) observed after 21 days. Similarly, ERFD activity in renal microsomes was increased (200% of donor) after 21 days. Both pulmonary and renal microsomal P450 2B dependent 7-pentoxyresorufin O-depentylation (PRFD) activity was decreased (50 and 75% of donor) 1 day after transplantation but was essentially unchanged 3, 7, and 21 days after transplantation. Pulmonary and renal microsomal heme oxygenase activities were not significantly affected by liver transplantation. In contrast, total hepatic microsomal P450 concentrations were decreased maximally (to 45% of donor concentration) 7 days after transplantation and remained low (55% of donor) up to 21 days. Similarly, hepatic P450 1A dependent ERFD and P450 2B dependent PRFD activities were maximally depressed (20 and 25% of donor activities) after 7 days and remained low (75 and 30% of donor) up to 21 days after transplantation. The decreases in rates of hepatic P450 monooxygenation were accompanied by significant increases in microsomal heme oxygenase activity. The data presented in this study suggest the existence of generalized stress responses to inflammation that result in tissue- and isozyme-selective modulation of P450 monooxygenase activity.(ABSTRACT TRUNCATED AT 250 WORDS)
尽管肝移植一直是深入研究的课题，但关于该手术对外源物质代谢的影响，人们所知相对较少。本研究的目的是通过使用同工酶选择性底物，检测原位肝移植对大鼠肝、肺和肾微粒体细胞色素P450（P450）单加氧酶活性的影响。受体大鼠肺微粒体中P450 1A1依赖的7-乙氧基试卤灵O-脱乙基化（ERFD）活性随时间增加，在21天后观察到最大诱导（为供体的750%）。同样，肾微粒体中的ERFD活性在21天后增加（为供体的200%）。肺和肾微粒体中P450 2B依赖的7-戊氧基试卤灵O-脱戊基化（PRFD）活性在移植后1天降低（分别为供体的50%和75%），但在移植后3天、7天和21天基本未变。肝移植对肺和肾微粒体血红素加氧酶活性无显著影响。相反，肝微粒体总P450浓度在移植后7天最大程度降低（降至供体浓度的45%），直至21天一直维持在较低水平（为供体的55%）。同样，肝P450 1A依赖的ERFD和P450 2B依赖的PRFD活性在7天后最大程度降低（分别为供体活性的20%和25%），直至移植后21天一直维持在较低水平（分别为供体的75%和30%）。肝P450单加氧反应速率的降低伴随着微粒体血红素加氧酶活性的显著增加。本研究呈现的数据表明，存在对炎症的全身性应激反应，导致P450单加氧酶活性的组织和同工酶选择性调节。（摘要截短至250字）
