Gilbert E A, Edwards R J, Boobis A R, Rose S, Jenner P
Neurodegenerative Diseases Research Centre, Guy's King's and St Thomas' School of Biomedical Sciences, King's College, London, UK.
J Neural Transm (Vienna). 2003 Oct;110(10):1091-101. doi: 10.1007/s00702-003-0029-3.
Genetic susceptibility to toxin action leading to nigral cell degeneration in Parkinson's disease (PD) may be dictated by the activity of P450 enzymes in brain. In adult rat brain only CYP2C13/6, CYP2D2, CYP2D5 are found in the substantia nigra. However, little is known concerning the isoforms present in foetal dopaminergic ventral mesencephalon (VM) tissues commonly used to study toxin action. In this investigation, we have determined the expression of P450 enzymes in foetal (VM) slices and in primary cultures of this region. In foetal VM sections immunoreactivity was observed for CYP2C13/6, CYP2D1, CYP2D3, CYP2D4, CYP2D5 and OR. There was no expression of CYP1A2, CYP2B1/2, CYP2C12, CYP2D2 and CYP2E1. In cultured foetal rat VM, immunoreactivity was observed for all P450 enzymes examined, namely CYP1A2, CYP2B1/2, CYP2C13/6, CYP2C12, CYP2D1, CYP2D2, CYP2D3, CYP2D4, CYP2D5, CYP2E1 and OR. There were marked differences in the degree of expression of the isoforms of P450, for example CYP2D1 was only weakly expressed in foetal VM sections but expression was strong in VM cultures. The difference between VM slices and primary cultures suggests that the culturing process can induce some P450 enzymes. CYP2D1, CYP2D3, CYP2D4 were expressed in the foetal VM but were not present in adult rat substantia nigra. Further investigation is now required to determine the functional implications as they may confer an altered level of susceptibility to neurotoxins between foetal and adult dopaminergic cells.
导致帕金森病（PD）中黑质细胞变性的毒素作用的遗传易感性可能由脑中P450酶的活性决定。在成年大鼠脑中，仅在黑质中发现CYP2C13/6、CYP2D2、CYP2D5。然而，关于常用于研究毒素作用的胎儿多巴胺能腹侧中脑（VM）组织中存在的同工型，人们了解甚少。在本研究中，我们测定了胎儿（VM）切片和该区域原代培养物中P450酶的表达。在胎儿VM切片中，观察到CYP2C13/6、CYP2D1、CYP2D3、CYP2D4、CYP2D5和OR的免疫反应性。未观察到CYP1A2、CYP2B1/2、CYP2C12、CYP2D2和CYP2E1的表达。在培养的胎儿大鼠VM中，观察到所有检测的P450酶的免疫反应性，即CYP1A2、CYP2B1/2、CYP2C13/6、CYP2C12、CYP2D1、CYP2D2、CYP2D3、CYP2D4、CYP2D5、CYP2E1和OR。P450同工型的表达程度存在显著差异，例如CYP2D1在胎儿VM切片中仅弱表达，但在VM培养物中表达较强。VM切片和原代培养物之间的差异表明培养过程可诱导一些P450酶。CYP2D1、CYP2D3、CYP2D4在胎儿VM中表达，但在成年大鼠黑质中不存在。现在需要进一步研究以确定其功能意义，因为它们可能导致胎儿和成年多巴胺能细胞对神经毒素的易感性水平改变。
