Induction of the drug metabolizing enzyme CYP2D in monkey brain by chronic nicotine treatment
Induction of the drug metabolizing enzyme CYP2D in monkey brain by chronic nicotine treatment
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DOI：
10.1016/j.neuropharm.2008.07.017
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发表时间：
2008-12-01
影响因子：
4.7
通讯作者：
Tyndale, Rachel F.
中科院分区：
文献类型：
--
作者：
Mann, Amandeep;Miksys, Sharon;Tyndale, Rachel F.
细胞色素 P450 (CYP) 2D6 是一种存在于肝脏和大脑中的酶，参与多种中枢作用药物（例如抗抑郁药、精神安定药、阿片类药物）、内源性神经化学物质（例如儿茶酚胺）的代谢以及神经毒素（例如杀虫剂、1-甲基-4-苯基-1,2,3,6-四氢吡啶）的灭活（MPTP））。尽管 CYP2D6 本质上是肝脏中的一种不可诱导酶，但我们发现吸烟者的大脑中，尤其是基底神经节中，有较高的 CYP2D6。为了确定香烟烟雾中的尼古丁是否会增加大脑 CYP2D），对非洲绿猴进行长期尼古丁治疗（0.05 mg/kg，持续 2 天，然后 0.15 mg/kg，持续 2 天，然后 0.3 mg/kg，持续 18 天，皮下注射，每日两次）。通过蛋白质印迹和免疫细胞化学检测，与盐水处理的动物相比，接受尼古丁处理的猴子大脑中 CYP2D 显着诱导。在尼古丁治疗的猴子中没有观察到肝脏 CYP2D 的变化。在各个大脑区域都观察到了诱导作用，包括帕金森病 (PD) 受影响的区域，例如黑质（3 倍，p = 0.01）、壳核（2.1 倍，p = 0.001）和脑干（2.4 倍，p = 0.001），其中尾状核接近显着性（1.6 倍，p = 0.07）。免疫细胞化学揭示，经盐水和尼古丁处理的猴子中 CYP2D 的表达具有细胞特异性，特别是在小脑、额叶皮层和海马中。这些结果表明，猴脑表达 CYP2D，这是在长期尼古丁治疗后在特定细胞和大脑区域中诱导的。吸烟者或使用尼古丁治疗的人的大脑 CYP2D6 水平可能较高，这可能会导致局部中枢神经系统药物代谢改变和神经毒素失活。 (C) 2008 Elsevier Ltd. 保留所有权利。
Cytochrome P450 (CYP) 2D6, an enzyme found in the liver and the brain, is involved in the metabolism of numerous centrally acting drugs (e.g. antidepressants, neuroleptics, opiates), endogenous neurochemicals (e.g. catecholamines) and in the inactivation of neurotoxins (e.g. pesticides, 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)). Although CYP2D6 is essentially an uninducible enzyme in the liver, we show that smokers have higher CYP2D6 in the brain, especially in the basal ganglia. In order to determine whether nicotine, a component of cigarette smoke, could increase brain CYP2D), African Green monkeys were treated chronically with nicotine (0.05 mg/kg for 2 days, then 0.15 mg/kg for 2 days followed by 0.3 mg/kg for 18 days s.c., b.i.d.). Monkeys treated with nicotine showed significant induction of CYP2D in brain when compared to saline-treated animals as detected by western blotting and immunocytochemistry. No changes in liver CYP2D were observed in nicotine-treated monkeys. Induction was observed in various brain regions including those affected in Parkinson's disease (PD) such as substantia nigra (3-fold, p = 0.01), putamen (2.1-fold, p = 0.001) and brainstem (2.4-fold, p = 0.001), with the caudate nucleus approaching significance (1.6-fold, p = 0.07). Immunocytochernistry revealed that the expression of CYP2D in both saline- and nicotine-treated monkeys is cell-specific particularly in the cerebellum, frontal cortex and hippocampus. These results suggest that monkey brain expresses CYP2D which is induced in specific cells and brain regions upon chronic nicotine treatment. Smokers, or those using nicotine treatment, may have higher levels of brain CYP2D6 that may result in altered localized CNS drug metabolism and inactivation of neurotoxins. (C) 2008 Elsevier Ltd. All rights reserved.