Activation of the Acute Inflammatory Response Alters Cytochrome P450 Expression and Eicosanoid Metabolism
Activation of the Acute Inflammatory Response Alters Cytochrome P450 Expression and Eicosanoid Metabolism
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DOI：
10.1124/dmd.110.035287
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发表时间：
2011-01-01
影响因子：
3.9
通讯作者：
Lee, Craig R.
中科院分区：
文献类型：
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作者：
Theken, Katherine N.;Deng, Yangmei;Lee, Craig R.
细胞色素 P450 (P450) 介导的花生四烯酸代谢调节肝脏和肝外组织的炎症。 CYP2C/CYP2J 衍生的环氧二十碳三烯酸和二羟基二十碳三烯酸 (EET+DHET) 具有抗炎作用，而 CYP4A/CYP4F 衍生的 20-羟基二十碳四烯酸 (20-HETE) 具有促炎作用。由于炎症对 P450 介导的内源类二十烷酸形成的影响尚不清楚，因此我们评估了腹膜内脂多糖 (LPS) (1 mg/kg) 或盐水给药后 3、6、24 和 48 小时小鼠肝脏、肾脏、肺和心脏中 P450 mRNA 水平以及 P450 环氧化酶 (EET+DHET) 和 omega-羟化酶 (20-HETE) 代谢活性。 LPS 给药后 24 小时和 48 小时，肝脏 Cyp2c29、Cyp2c44 和 Cyp2j5 mRNA 水平以及 EET+DHET 形成显着降低。肝脏 Cyp4a12a、Cyp4a12b 和 Cyp4f13 mRNA 水平和 20-HETE 形成在 24 小时时也显着降低，但在 48 小时时恢复至基线，导致 20-HETE/EET+DHET 形成率比值显着高于盐水处理小鼠。 LPS 处理 24 小时后，肾 P450 mRNA 水平和 P450 介导的类二十烷酸代谢同样受到抑制。 LPS 给药后所有时间点的肺部 EET+DHET 形成均较低，而 20-HETE 形成以时间依赖性方式受到抑制，在 24 小时观察到形成率最低。在心脏中未观察到 EET+DHET 或 20-HETE 形成的差异。总的来说，这些数据表明，先天免疫反应的急性激活会以异构体、组织和时间依赖性方式改变小鼠体内的 P450 表达和类二十烷酸代谢。需要进一步研究来确定 P450 环氧化酶和 omega-羟化酶途径之间功能平衡的治疗恢复是否是一种有效的抗炎策略。
Cytochrome P450 (P450)-mediated metabolism of arachidonic acid regulates inflammation in hepatic and extrahepatic tissue. CYP2C/CYP2J-derived epoxyeicosatrienoic and dihydroxyeicosatrienoic acids (EET+DHET) elicit anti-inflammatory effects, whereas CYP4A/CYP4F-derived 20-hydroxyeicosatetraenoic acid (20-HETE) is pro-inflammatory. Because the impact of inflammation on P450-mediated formation of endogenous eicosanoids is unclear, we evaluated P450 mRNA levels and P450 epoxygenase (EET+DHET) and omega-hydroxylase (20-HETE) metabolic activity in liver, kidney, lung, and heart in mice 3, 6, 24, and 48 h after intraperitoneal lipopolysaccharide (LPS) (1 mg/kg) or saline administration. Hepatic Cyp2c29, Cyp2c44, and Cyp2j5 mRNA levels and EET+DHET formation were significantly lower 24 and 48 h after LPS administration. Hepatic Cyp4a12a, Cyp4a12b, and Cyp4f13 mRNA levels and 20-HETE formation were also significantly lower at 24 h, but recovered to baseline at 48 h, resulting in a significantly higher 20-HETE/EET+DHET formation rate ratio compared with that for saline-treated mice. Renal P450 mRNA levels and P450-mediated eicosanoid metabolism were similarly suppressed 24 h after LPS treatment. Pulmonary EET+DHET formation was lower at all time points after LPS administration, whereas 20-HETE formation was suppressed in a time-dependent manner, with the lowest formation rate observed at 24 h. No differences in EET+DHET or 20-HETE formation were observed in heart. Collectively, these data demonstrate that acute activation of the innate immune response alters P450 expression and eicosanoid metabolism in mice in an isoform-, tissue-, and time-dependent manner. Further study is necessary to determine whether therapeutic restoration of the functional balance between the P450 epoxygenase and omega-hydroxylase pathways is an effective anti-inflammatory strategy.