Riedl A G, Watts P M, Edwards R J, Schulz-Utermoehl T, Boobis A R, Jenner P, Marsden C D
Neurodegenerative Diseases Research Centre, Pharmacology Group, Biomedical Sciences Division, King's College, Manresa Road, London SW3 6LX, UK.
Brain Res. 1999 Mar 20;822(1-2):175-91. doi: 10.1016/s0006-8993(99)01113-0.
P450 enzymes in the CYP2D subfamily have been suggested to contribute to the susceptibility of individuals in developing Parkinson's disease. We have used specific anti-peptide antisera and peroxidase immunohistochemistry to investigate the expression of CYP2D enzymes in the rat brain and some possible factors that may affect their regulation. In male Wistar rats, CYP2D1 was not detected in the basal ganglia or in any other brain region. CYP2D2 was weakly expressed within neurones of the subthalamic nucleus, substantia nigra and interpeduncular nucleus as well as in the hippocampus, dentate gyrus, red nucleus and pontine nucleus. CYP2D3 and CYP2D4 were absent from the basal ganglia, although moderate amounts of CYP2D3 were detected within fibres of the oculomotor root, and very low levels of CYP2D4 were present in white matter tracts. In contrast, CYP2D5 was extensively expressed in the basal ganglia, including neurones in the subthalamic nucleus, substantia nigra and interpeduncular nucleus, as well as other areas of the brain, including the ventral tegmental area, piriform cortex, hippocampus, dentate gyrus, medial habenular nucleus, thalamic nucleus and pontine nucleus. Lesioning of the nigro-striatal tract to cause almost a complete loss of tyrosine hydroxylase containing neurones in the substantia nigra, also reduced the number of neurones expressing CYP2D5 by 50%, indicating that CYP2D5 is expressed in dopaminergic neurones. Castration of pre-pubertal or adult Wistar rats had no effect on the number of CYP2D5-positive neurones in the substantia nigra. Although Dark Agouti rats lack hepatic CYP2D2, expression in the midbrain was similar to that of Wistar rats; furthermore, there was no difference in expression or distribution between male and female rats. In contrast to naive rats, extensive expression of CYP2D4 was found throughout the basal ganglia and in other brain nuclei in Wistar rats treated with not only clozapine, but also saline, suggesting that CYP2D4 may be induced as a result of mild stress. The function of CYP2D enzymes in the brain remains unknown, but their selective localisation suggests a physiological role in neuronal activity and in adaptation to abnormal situations.
CYP2D亚家族中的细胞色素P450酶被认为与个体患帕金森病的易感性有关。我们使用特异性抗肽抗血清和过氧化物酶免疫组织化学方法来研究CYP2D酶在大鼠脑中的表达以及一些可能影响其调节的因素。在雄性Wistar大鼠中，基底神经节或其他任何脑区均未检测到CYP2D1。CYP2D2在丘脑底核、黑质和脚间核的神经元中以及海马、齿状回、红核和脑桥核中弱表达。基底神经节中未检测到CYP2D3和CYP2D4，不过在动眼神经根纤维中检测到适量的CYP2D3，白质束中存在极低水平的CYP2D4。相比之下，CYP2D5在基底神经节中广泛表达，包括丘脑底核、黑质和脚间核的神经元，以及脑的其他区域，包括腹侧被盖区、梨状皮质、海马、齿状回、内侧缰核、丘脑核和脑桥核。黑质纹状体束损伤导致黑质中几乎完全丧失含酪氨酸羟化酶的神经元，同时表达CYP2D5的神经元数量也减少了50%，这表明CYP2D5在多巴胺能神经元中表达。对青春期前或成年Wistar大鼠进行阉割对黑质中CYP2D5阳性神经元的数量没有影响。尽管深色刺豚鼠缺乏肝脏CYP2D2，但中脑的表达与Wistar大鼠相似；此外，雄性和雌性大鼠在表达或分布上没有差异。与未处理的大鼠相比，不仅用氯氮平处理，还用生理盐水处理的Wistar大鼠的整个基底神经节和其他脑核中均发现CYP2D4广泛表达，这表明CYP2D4可能是轻度应激的结果而被诱导。脑中CYP2D酶的功能仍然未知，但其选择性定位表明其在神经元活动和适应异常情况中具有生理作用。
