Cytochrome P450 expression and regulation in the brain

Abstract

The regulation of brain cytochrome P450 enzymes (CYPs) is different compared with respective hepatic enzymes. This may result from anatomical bases and physiological functions of the two organs. The brain is composed of a variety of functional structures built of different interconnected cell types endowed with specific receptors that receive various neuronal signals from other brain regions. Those signals activate transcription factors or alter functioning of enzyme proteins. Moreover, the blood-brain barrier (BBB) does not allow free penetration of all substances from the periphery into the brain. Differences in neurotransmitter signaling, availability to endogenous and exogenous active substances, and levels of transcription factors between neuronal and hepatic cells lead to differentiated expression and susceptibility to the regulation of CYP genes in the brain and liver. Herein, we briefly describe the CYP enzymes of CYP1-3 families, their distribution in the brain, and discuss brain-specific regulation of CYP genes. In parallel, a comparison to liver CYP regulation is presented. CYP enzymes play an essential role in maintaining the levels of bioactive molecules within normal ranges. These enzymes modulate the metabolism of endogenous neurochemicals, such as neurosteroids, dopamine, serotonin, melatonin, anandamide, and exogenous substances, including psychotropics, drugs of abuse, neurotoxins, and carcinogens. The role of these enzymes is not restricted to xenobiotic-induced neurotoxicity, but they are also involved in brain physiology. Therefore, it is crucial to recognize the function and regulation of CYP enzymes in the brain to build a foundation for future medicine and neuroprotection and for personalized treatment of brain diseases.

The Reduction of the Combined Effects of Aflatoxin and Ochratoxin A in Piglet Livers and Kidneys by Dietary Antioxidants

“…Previous works have demonstrated that CYP3A constitutive expression is regulated by nuclear transcription factor Y; specificity protein 1 [81,82]; hepatocyte nuclear factors 1α, 3γ and 4 [83][84][85]; upstream stimulatory factor 1 [86]; activator protein 1 [87] and CCAAT/enhancer-binding proteins α and β [85,86]. In the presence of xenobiotics, induced expression of CYP3A is mediated by Pregnane X Receptor [80], constitutive androstane receptor (CAR), glucocorticoid receptor (GR) and vitamin D receptor (VDR) [81,88,89].…”

Benzo[a]pyrene impairs the migratory pattern of human gonadotropin-releasing-hormone-secreting neuroblasts

“… 24 The strong induction of both isoforms after BaP exposure indicates that FNCB4 cells may be a direct target of the EDC, which therefore affects the gonadal function not only peripherally but also at the brain level. Indeed, a constitutive expression of CYP1A1 has been reported for neuronal and olfactory bulb cells, 25 , 26 as well as CYP1B1 is highly expressed in extrahepatic organs 27 including fetal brain. 28 Concerning the impact of BaP on FNCB4 phenotype and function, we found negative effects on the expression of cell migration-related genes, such as FGFR1, NRP2 and ETB, with no GnRH mRNA changes.…”

Role of Vitamin D in Cognitive Dysfunction: New Molecular Concepts and Discrepancies between Animal and Human Findings

“…In the brain, the expression of CYP2R1 was demonstrated in pericytes, which may play a significant role in regulating the permeability of the BBB for vitamin D metabolites and suggests the existence of a neurovascular vitamin D autocrine/paracrine system [63]. Furthermore, CYP3A4 also shows a cell type-and region-specific expression in the brain which might have new roles beyond drug clearance [64,65].…”