Expression of constitutive and inducible cytochrome P450 2E1 in rat brain
Expression of constitutive and inducible cytochrome P450 2E1 in rat brain
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DOI：
10.1007/s11010-005-9109-z
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发表时间：
2006-06-01
影响因子：
4.3
通讯作者：
Parmar, Devendra
中科院分区：
文献类型：
--
作者：
Yadav, Sanjay;Dhawan, Alok;Parmar, Devendra
开始研究细胞色素P450 2 E1（CYP 2 E1）在大鼠脑中的表达的研究表明，在对照大鼠脑中蛋白和mRNA表达较低，但可检测到。虽然脑中CYP 2 E1的mRNA和蛋白表达比肝脏低几倍，但在对照大鼠脑微粒体中观察到相对较高的N-亚硝基二甲胺脱甲基酶（NDMA-d）活性。与肝脏一样，用CYP 2 E1诱导剂（如乙醇或吡唑或丙酮）预处理可显著增加脑微粒体NDMA-d的活性。动力学研究还显示，由于从乙醇预处理大鼠中分离的脑微粒体中CYP 2 E1的表达增加，底物对脑酶的Vmax和亲和力（Km）增加。在体外研究中，使用CYP 2 E1和抗CYP 2 E1特异性有机抑制剂显著抑制脑NDMA-d活性，表明与肝脏一样，大鼠脑中的NDMA-d活性由CYP 2 E1催化。对照组大鼠嗅叶CYP 2 E1表达和催化活性最高。乙醇预处理后，小脑和海马中CYP 2 E1的mRNA表达和活性增加数倍，而嗅叶中的表达和活性增加相对较小，其他脑区无明显变化，表明CYP 2 E1诱导可能参与了这些脑区对乙醇诱导的自由基损伤和神经元变性的选择性敏感性。
Studies initiated to investigate the expression of cytochrome P450 2E1 (CYP2E1) in rat brain demonstrated low but detectable protein and mRNA expression in control rat brain. Though mRNA and protein expression of CYP2E1 in brain was several fold lower as compared to liver, relatively high activity of N-nitrosodimethylamine demethylase (NDMA-d) was observed in control rat brain microsomes. Like liver, pretreatment with CYP2E1 inducers such as ethanol or pyrazole or acetone significantly increased the activity of brain microsomal NDMA-d. Kinetic studies also showed an increase in the Vmax and affinity (Km) of the substrate towards the brain enzyme due to increased expression of CYP2E1 in microsomes of brain isolated from ethanol pretreated rats. In vitro studies using organic inhibitors, specific for CYP2E1 and anti-CYP2E1 significantly inhibited the brain NDMA-d activity indicating that like liver, NDMA-d activity in rat brain is catalyzed by CYP2E1. Olfactory lobes exhibited the highest CYP2E1 expression and catalytic activity in control rats. Furthermore, several fold increase in the mRNA expression and activity of CYP2E1 in cerebellum and hippocampus while a relatively small increase in the olfactory lobes and no significant change in other brain regions following ethanol pretreatment have indicated that CYP2E1 induction maybe involved in selective sensitivity of these brain areas to ethanol induced free radical damage and neuronal degeneration.