Evidence for induced microsomal bilirubin degradation by cytochrome P450 2A5
Evidence for induced microsomal bilirubin degradation by cytochrome P450 2A5
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DOI：
10.1016/j.bcp.2005.08.009
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发表时间：
2005-11-15
影响因子：
5.8
通讯作者：
Lang, MA
中科院分区：
文献类型：
--
作者：
Abu-Bakar, A;Moore, MR;Lang, MA
胆红素（BR）的氧化代谢-血红素的分解产物，具有细胞保护和毒性特性-是除葡萄糖醛酸化之外的重要解毒途径。参与这种氧化降解的主要酶尚不清楚。在本文中，我们提出了一个主要作用的肝细胞色素P450 2A5（Cyp2a5）在BR降解镉中毒，其中BR水平升高诱导血红素加氧酶-1（HO-1）的证据。CdCl2处理DBA/2J小鼠后，CYP 2a5和HO-1表达均增加，微粒体BR降解活性增强。与此相反，总细胞色素P450（CYP）含量和Cyp1a2的表达下调的处理。HO-1和Cyp2a5的诱导在mRNA、蛋白和酶活性水平上是实质性的。在每种情况下，HO-1的上调之前，Cyp2a5的5 - 10小时的间隔。BR完全抑制微粒体Cyp2a5依赖性香豆素羟化酶活性，IC 50约等于底物浓度。7-甲氧基试卤灵7-O-脱甲基酶（MROD）的活性，主要由Cyp1a2催化，被BR抑制高达36%。微粒体BR降解被香豆素和抗Cyp2a5的单克隆抗体抑制约90%。此外，7-甲氧基试卤灵，Cyp1a2的底物，抑制BR降解活性约20%。总之，结果强烈表明Cyp2a5在BR的氧化降解中起主要作用。其次，在镉介导的损伤过程中，HO-1和Cyp2a5的协调上调暗示了酶系统网络在维持BR产生和消除的平衡中的作用。(c)2005年爱思唯尔公司All rights reserved.
Oxidative metabolism of bilirubin (BR) - a breakdown product of haem with cytoprotective and toxic properties - is an important route of detoxification in addition to glucuronidation. The major enzyme(s) involved in this oxidative degradation are not known. In this paper, we present evidence for a major role of the hepatic cytochrome P450 2A5 (Cyp2a5) in BR degradation during cadmium intoxication, where the BR levels are elevated following induction of haem oxygenase-1 (HO-1). Treatment of DBA/2J mice with CdCl2 induced both the Cyp2a5 and HO-1, and increased the microsomal BR degradation activity. By contrast, the total cytochrome P450 (CYP) content and the expression of Cyp1a2 were down-regulated by the treatment. The induction of the HO-1 and Cyp2a5 was substantial at the mRNA, protein and enzyme activity levels. In each case, the up-regulation of HO-1 preceded that of Cyp2a5 with a 5-10 h interval. BR totally inhibited the microsomal Cyp2a5-dependent coumarin hydroxylase activity, with an IC50 approximately equal to the substrate concentration. The 7-methoxyresorufin 7-O-demethylase (MROD) activity, catalyzed mainly by the Cyp1a2, was inhibited up to 36% by BR. The microsomal BR degradation was inhibited by coumarin and a monoclonal antibody against the Cyp2a5 by about 90%. Furthermore, 7-methoxyresorufin, a substrate for the Cyp1a2, inhibited BR degradation activity by approximately 20%. In sum, the results strongly suggest a major role for Cyp2a5 in the oxidative degradation of BR. Secondly, the coordinated up-regulation of the HO-1 and Cyp2a5 during Cd-mediated injury implicates a network of enzyme systems in the maintenance of balancing BR production and elimination. (c) 2005 Elsevier Inc. All rights reserved.