Hepatic cytochrome p450 gene regulation during endotoxin-induced inflammation in nuclear receptor knockout mice
Hepatic cytochrome p450 gene regulation during endotoxin-induced inflammation in nuclear receptor knockout mice
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DOI：
10.1124/jpet.105.085456
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发表时间：
2005-08-01
影响因子：
3.5
通讯作者：
Morgan, ET
中科院分区：
文献类型：
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作者：
Richardson, TA;Morgan, ET
炎症因子如脂多糖（LPS）下调许多细胞色素P450（P450）mRNA和蛋白质的肝脏表达。先前的研究表明，抑制某些P450 mRNA可能涉及核受体过氧化物酶体增殖物激活受体α（PPAR α）或β-内酰胺酶X受体（PXR）的调节或调制。为了确定这些受体在P450下调中的参与程度，对PPARalpha敲除（KO）、PXR KO和适当的野生型（WT）小鼠给予盐水或1 mg/kg LPS。16 h后检测几种P450亚型、白细胞介素（IL）-1 β、IL-6、肿瘤坏死因子（TNF）α、α 1-酸性糖蛋白（AGP）和纤维蛋白原（FBG）的肝脏mRNA和蛋白表达。LPS给药显著降低了两组PPAR α和PXR小鼠中CYP 1A 2、2A 5、2C 29、2 E1、3A 11、4A 10和4A 14 mRNA的肝脏表达，而PPAR α WT和KO小鼠中CYP 3A 13 mRNA略有增加，但PXR小鼠中没有。LPS给药对小鼠肝P450蛋白（使用大鼠P450 2C、3A、4A和2 E抗体探测）的影响在大多数情况下与mRNA结果一致。LPS处理显著增加了PPAR α和PXR小鼠中的IL-1 β、IL-6、TNF α、AGP和FBG mRNA，其中TNF α的作用最大。由于两种核受体的P450 mRNA表达的降低在WT和KO小鼠中基本相同，这些数据表明炎症期间P450的下调不需要核受体PPAR α和PXR。
Inflammatory agents such as lipopolysaccharide (LPS) down-regulate the hepatic expression of many cytochrome P450 ( P450) mRNAs and proteins. Previous studies suggested that suppression of some P450 mRNAs could involve the regulation or modulation of the nuclear receptors peroxisome proliferator-activated receptor alpha( PPAR alpha) or pregnane X receptor (PXR). To determine the involvement of these receptors in P450 down-regulation, PPAR alpha knockout ( KO), PXR KO, and appropriate wild-type (WT) mice were administered either saline or 1 mg/kg LPS. Hepatic mRNA and protein expression of several P450 isoforms, interleukin (IL)-1 beta, IL-6, tumor necrosis factor (TNF)alpha, alpha 1-acid glycoprotein (AGP), and fibrinogen (FBG) were examined 16 h later. LPS administration significantly decreased the hepatic expression of CYP1A2, 2A5, 2C29, 2E1, 3A11, 4A10, and 4A14 mRNAs in both groups of PPAR alpha and PXR mice, whereas CYP3A13 mRNA was increased slightly in PPAR alpha WT and KO mice, but not in PXR mice. Effects of LPS administration on mouse hepatic P450 proteins ( probed using rat P450 2C, 3A, 4A, and 2E antibodies) were consistent with mRNA results in most cases. LPS treatment significantly increased IL-1 beta, IL-6, TNF alpha, AGP, and FBG mRNA in both PPAR alpha and PXR mice, with the greatest effect observed with TNF alpha. Because decreases in P450 mRNA expression were essentially identical in both WT and KO mice for both nuclear receptors, these data indicate that down-regulation of P450 during inflammation does not require the nuclear receptors PPAR alpha and PXR.