Hedlund E, Gustafsson J A, Warner M
Department of Medical Nutrition, Huddinge University Hospital, Novum, Sweden.
Curr Drug Metab. 2001 Sep;2(3):245-63. doi: 10.2174/1389200013338513.
After many frustrating decades of unsuccessful attempts to characterize the isoforms of P450 in the brain, several scientific breakthroughs in the 80s and 90s have resulted in major advances in our understanding of cytochromes P450 (CYP) in brain. We now know that classical CYP inducers, e.g. phenobarbital and pregnenolone 16alpha-carbonitrile, which regulate drug-metabolizing enzymes in the liver, are specific ligands for ligand-activated transcription factors, and that the brain content of many of these transcription factors is low. This explains why these inducers have little effect on brain CYP content. The most effective inducers of brain P450 are some of the CNS active drugs and solvents. The level of CYPs in brain, approximately 0.5-2% of that in liver, is too low to significantly influence the overall pharmacokinetics of drugs and hormones in the body. Instead CYPs appear to have specific functions in brain, e.g. regulation of the levels of endogenous GABAA receptor agonists maintenance of brain cholesterol homeostasis and elimination of retinoids The novel CYPs which catalyse these reactions have recently been characterized. They are abundantly expressed in the brain confirming what has been previously found, i.e. that the major hepatic, adrenal and gonadal CYP isozymes contribute very little to the overall content of CYP in brain. It is not clear what fraction of brain CYP has been characterized, although a complete characterization of constitutive and induced CYPs in brain is essential for understanding the role of these enzymes in brain physiology as well as in age-related and xenobiotic-induced neurotoxicity.
在经历了数十年对大脑中细胞色素P450同工型进行表征的无果尝试后，20世纪80年代和90年代的几项科学突破使我们对大脑中细胞色素P450（CYP）的理解取得了重大进展。我们现在知道，经典的CYP诱导剂，如苯巴比妥和孕烯醇酮16α-腈，它们在肝脏中调节药物代谢酶，是配体激活转录因子的特异性配体，而且这些转录因子在大脑中的含量很低。这就解释了为什么这些诱导剂对大脑CYP含量影响很小。大脑P450最有效的诱导剂是一些中枢神经系统活性药物和溶剂。大脑中CYP的水平约为肝脏中的0.5 - 2%，太低以至于无法显著影响体内药物和激素的整体药代动力学。相反，CYP似乎在大脑中具有特定功能，例如调节内源性GABAA受体激动剂的水平、维持大脑胆固醇稳态以及清除视黄醛。催化这些反应的新型CYP最近已被表征。它们在大脑中大量表达，证实了之前的发现，即主要的肝脏、肾上腺和性腺CYP同工酶对大脑中CYP的整体含量贡献很小。虽然目前尚不清楚大脑中已被表征的CYP占比多少，但全面表征大脑中组成型和诱导型CYP对于理解这些酶在大脑生理学以及与年龄相关和外源性物质诱导的神经毒性中的作用至关重要。
