Hypoxia-induced down-regulation of CYP1A1/1A2 and up-regulation of CYP3A6 involves serum mediators
Hypoxia-induced down-regulation of CYP1A1/1A2 and up-regulation of CYP3A6 involves serum mediators
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DOI：
10.1038/sj.bjp.0704933
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发表时间：
2002-11-01
影响因子：
7.3
通讯作者：
du Souich, P
中科院分区：
文献类型：
--
作者：
Fradette, C;Bleau, AM;du Souich, P
1急性中度缺氧改变肝细胞色素P450（P450）某些同工酶的催化活性和表达。本研究的目的是记录缺氧是否直接或通过释放血清介质影响肝脏P450。2将家兔置于FiO（2）为8%的环境中48 h，处死，分离血清和肝细胞;将来自对照和缺氧兔的肝细胞与来自对照和缺氧兔的血清孵育4和24小时，检测总P450含量，CYP 1A 1，1A 2和3A 6活性和表达进行了评估。通过尺寸排阻色谱法分离血清，并测试其改变P450活性和量的能力，并通过中和实验鉴定血清介质。3总血清和具有15-23和65-94 kDa M-r蛋白的组分降低P450含量和CYP 1A 1、1A 2和3A 6以及CYP 1A 1、1A 2和3A 6 mRNA的表达。总血清和具有32-44 kDa蛋白质的组分增加了CYP 3A 6活性、蛋白质和mRNA。与CYP 1A 1、1A 2和3A 6活性和表达降低有关的血清介质为干扰素-γ（IFN-γ）、白细胞介素-1 β（IL-1 β）和IL-2。促红细胞生成素（Epo）可使P450含量和CYP 3A 6表达增加。4综上所述，急性中度缺氧可降低CYP 1A 1，1A 2和CYP 1A 1，1A 2 mRNA的活性和表达，增加CYP 3A 6蛋白、活性和CYP 3A 6 mRNA。有几种机制导致P450的这些变化，其中包括作为血清介质的细胞因子的释放。
1 Acute moderate hypoxia modifies the catalytic activity and expression of certain isoenzymes of hepatic cytochrome P450 (P450). The aim of this study was to document whether hypoxia affects hepatic P450 directly or through the release of serum mediators.2 Rabbits were subjected to a FiO(2) of 8% for 48 h, sacrificed, and serum and hepatocytes were isolated; hepatocytes from control and rabbits with hypoxia were incubated with serum from control and hypoxic rabbits for 4 and 24 h, and total P450 content, CYP1A1, 1A2 and 3A6 activities and expressions were assessed. Sera were fractionated by size exclusion chromatography and fractions tested for their ability to modify activity and amount of P450, and serum mediators were identified through neutralization experiments.3 Total serum and fractions with proteins of 15-23 and 65-94 kDa of M-r reduced P450 content and expression of CYP1A1, 1A2 and 3A6, as well as CYP1A1, 1A2 and 3A6 mRNA. Total serum and the fraction with 32-44 kDa proteins increased CYP3A6 activity and protein and mRNA. The serum mediators implicated in the decrease in activity and expression of CYP1A1, 1A2 and 3A6 were interferon-gamma (IFN-gamma), interleukin-1beta (IL-1beta) and IL-2. Erythropoietin (Epo) was partly responsible for the increase in P450 content and CYP3A6 expression.4 In conclusion, acute moderate hypoxia diminishes the activity and expression of CYP1A1, 1A2 and CYP1A1, 1A2 mRNA, and increases CYP3A6 protein, activity and CYP3A6 mRNA. Several mechanisms contribute to these changes in P450, among them the release of cytokines acting as serum mediators.