Document Detail

Cellular localization and functional significance of CYP3A4 in the human epileptic brain.
MedLine Citation:
PMID:  21294720     Owner:  NLM     Status:  MEDLINE    
PURPOSE: Compelling evidence supports the presence of P450 enzymes (CYPs) in the central nervous system (CNS). However, little information is available on the localization and function of CYPs in the drug-resistant epileptic brain. We have evaluated the pattern of expression of the specific enzyme CYP3A4 and studied its co-localization with MDR1. We also determined whether an association exists between CYP3A4 expression and cell survival.
METHODS: Brain specimens were obtained from eight patients undergoing resection to relieve drug-resistant seizures or to remove a cavernous angioma. Each specimen was partitioned for either immunostaining or primary culture of human endothelial cells and astrocytes. Immunostaining was performed using anti-CYP3A4, MDR1, GFAP, or NeuN antibodies. High performance liquid chromatography-ultraviolet (HPLC-UV) analysis was used to quantify carbamazepine (CBZ) metabolism by these cells. CYP3A4 expression was correlated to DAPI) condensation, a marker of cell viability. Human embryonic kidney (HEK) cells were transfected with 4',6-diamidino-2-phenylindole (CYP3A4 to further evaluate the link between CYP3A4 levels, CBZ metabolism, and cell viability.
KEY FINDINGS: CYP3A4 was expressed by blood-brain barrier (BBB) endothelial cells and by the majority of neurons (75 ± 10%). Fluorescent immunostaining showed coexpression of CYP3A4 and MDR1 in endothelial cells and neurons. CYP3A4 expression inversely correlated with DAPI nuclear condensation. CYP3A4 overexpression in HEK cells conferred resistance to cytotoxic levels of carbamazepine. CYP3A4 levels positively correlated with the amount of CBZ metabolized.
SIGNIFICANCE: CYP3A4 brain expression is not only associated with drug metabolism but may also represent a cytoprotective mechanism. Coexpression of CYP3A4 and MDR1 may be involved in cell survival in the diseased brain.
Chaitali Ghosh; Nicola Marchi; Nirav K Desai; Vikram Puvenna; Mohammed Hossain; Jorge Gonzalez-Martinez; Andreas V Alexopoulos; Damir Janigro
Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural     Date:  2011-02-05
Journal Detail:
Title:  Epilepsia     Volume:  52     ISSN:  1528-1167     ISO Abbreviation:  Epilepsia     Publication Date:  2011 Mar 
Date Detail:
Created Date:  2011-03-14     Completed Date:  2011-05-09     Revised Date:  2014-09-21    
Medline Journal Info:
Nlm Unique ID:  2983306R     Medline TA:  Epilepsia     Country:  United States    
Other Details:
Languages:  eng     Pagination:  562-71     Citation Subset:  IM    
Copyright Information:
Wiley Periodicals, Inc. © 2011 International League Against Epilepsy.
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MeSH Terms
Anticonvulsants / pharmacokinetics,  therapeutic use
Apoptosis / physiology
Astrocytes / pathology*
Blood-Brain Barrier / physiology*
Brain / pathology*
Carbamazepine / pharmacokinetics
Child, Preschool
Cytochrome P-450 CYP3A / genetics,  metabolism*
Drug Resistance
Endothelial Cells / pathology*
Epilepsy, Temporal Lobe / drug therapy,  pathology*,  surgery
HEK293 Cells
Hemangioma, Cavernous, Central Nervous System / pathology,  surgery
Neurons / pathology*
P-Glycoprotein / metabolism*
Tuberous Sclerosis / pathology,  surgery
Grant Support
R01 NS043284/NS/NINDS NIH HHS; R01 NS043284-04/NS/NINDS NIH HHS; R01 NS049514/NS/NINDS NIH HHS; R01 NS049514-05/NS/NINDS NIH HHS; R21 HD057256/HD/NICHD NIH HHS; R21 HD057256/HD/NICHD NIH HHS; R21 HD057256-02/HD/NICHD NIH HHS
Reg. No./Substance:
0/ABCB1 protein, human; 0/Anticonvulsants; 0/P-Glycoprotein; 33CM23913M/Carbamazepine; EC protein, human; EC P-450 CYP3A

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