The blood-brain barrier (BBB) is composed of microvessel endothelial cells sealed by tight junctions and surrounded by pericytes, neuron endings and astrocyte foot processes. These form a dynamic neurovascular unit which is the first line of defence for the brain against unwanted compounds. The entry of many compounds into the brain, including numerous commercial drugs, is also restricted by ATPbinding cassette (ABC) efflux transporters, including Pglycoprotein [P-gp, ABCB1/multidrug resistance (MDR1)], several multidrug resistance-associated proteins (MRPs) (ABCCs) and breast cancer resistance protein (BCRP) (ABCG2), at the plasma membrane of brain microvessel Address correspondence and reprint requests to Xavier Declèves, PhD, INSERM U705 CNRS UMR 7157, Faculté de Pharmacie, 4 avenue de l'observatoire, Paris 75006, France. E-mail: xavier.decleves@univ-paris5.frAbbreviations used: ABC, ATP-binding cassette; AhR, aryl hydrocarbon receptor; BBB, blood-brain barrier; BCRP, breast cancer resistance protein; CAR, constitutive androstane receptor; C t , crossing-threshold; CYP, cytochromes P450; GFAP, glial fibrillary acidic protein; MDR, multidrug resistance; MRP, multidrug resistance-associated protein; NG2, neuronglial antigen 2; PECAM-1, platelet endothelial cell adhesion molecule 1; Pgp, P-glycoprotein; PXR, pregnane xenobiotic receptor; qPCR, quantitative PCR; SYP, synaptophysin; TBP, TATA box-binding protein. AbstractWe have established the expression patterns of the genes encoding ATP-binding cassette (ABC) transporters and cytochromes P450 (CYPs) at the adult human blood-brain barrier (BBB) using isolated brain microvessels and cortex biopsies from patients with epilepsia or glioma. Microvessel purity was checked by measuring the expression of genes encoding BBB markers: platelet endothelial cell adhesion molecule 1 (endothelial cells), glial fibrillary acidic protein (astrocytes), synaptophysin (neurons) and neuron-glial antigen 2 (NG2) (pericytes). ABCG2 [breast cancer resistance protein (BCRP)] and ABCB1 (MDR1) were the main ABC transporter genes expressed in microvessels, with 20 times more ABCG2 and 25 times more ABCB1 in microvessels than in the cortex. The CYP1B1 isoform represented over 80% of all the CYPs genes detected in microvessels. There were 14 times more CYP1B1 in microvessels than in the cortex, showing that CYP1B1 is mainly expressed at the BBB. p-glycoprotein (ABCB1), BCRP (ABCG2) and CYP1B1 proteins were found in microvessels by western blotting. The expression of genes encoding three transcription factors [pregnane xenobiotic receptor (PXR), constitutive androstane receptor (CAR), aryl hydrocarbon receptor (AhR)] was also investigated. The AhR gene, involved in the regulation of CYP1B1 expression, was highly expressed in brain microvessels, whereas PXR and CAR genes were almost undetected. This detailed pattern of ABC and CYPs gene expression at the human BBB provides useful information for understanding how their substrates enter the brain.

To study the association between Parkinson disease (PD) and 2 polymorphisms in ABCB1 among subjects enrolled in the French health system for agricultural workers (Mutualité Sociale Agricole), as well as the interaction between ABCB1 and organochlorine insecticides.

ABSTRACT:Cytochrome P450 (P450) enzymes and ATP-binding cassette (ABC) transporters modulate the transport and metabolism of both endogenous and exogenous substrates and could play crucial roles in the human brain. In this study, we report the transcript expression profile of seven ABC transporters (ABCB1, ABCC1-C5, and ABCG2), 24 P450s (CYP1, CYP2, and CYP3 families and CYP46A1), and 14 related transcription factors [aryl hydrocarbon receptor, nuclear receptor (NR)1I2/pregnane X receptor, NR1I3/constitutive androstane receptor and NR1C/peroxisome proliferator-activated receptor, NR1H/liver X receptor, NR2B/retinoid X receptor, and NR3A/estrogen receptor subfamilies] in the whole brain, the dura mater, and 17 different encephalic areas. In addition, Western blotting and immunohistochemistry analysis were used to characterize the distribution of the P450s at the cellular and subcellular levels in some brain regions. Our results show the presence of a large variety of xenobiotic transporters and metabolizing enzymes in human brain and show for the first time their apparent selective distribution in different cerebral regions. The most abundant transporters were ABCC5 and ABCG2, which, interestingly, had a higher mRNA expression in the brain compared with that found in the liver. CYP46A1, CYP2J2, CYP2U1, CYP1B1, CYP2E1, and CYP2D6 represented more than 90% of the total P450 and showed selective distribution in different brain regions. Their presence in both microsomal and mitochondrial fractions was shown both in neuronal and glial cells in several brain areas. Thus, our study shows key enzymes of cholesterol and fatty acid metabolism to be present in the human brain and provides novel information of importance for elucidation of enzymes responsible for normal and pathological processes in the human brain.The cytochrome P450 (P450) enzymes belonging to families 1 through 3 and many ATP-binding cassette (ABC) transporters are primarily known for their role in xenobiotic transport and metabolism. These proteins exert their activity mainly in the liver but have also been found in other tissues such as lung, kidney, intestine, placenta, and brain. The extrahepatic localization of these proteins suggests important and unrecognized activities toward endogenous substrates. We hypothesize that the roles of these proteins in transport and metabolism both of endogenous and endogenous compounds are important in the human brain, but at present there is a significant lack of knowledge regarding the distribution of P450s and ABC transporters throughout the human brain.This work was supported by a grant from Servier Technology. Article, publication date, and citation information can be found at