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Xenobiotic-Metabolizing Enzymes and Transporters in the Normal Human Brain: Regional and Cellular Mapping as a Basis for Putative Roles in Cerebral Function

Université Paris Descartes, Paris, France (F.D., S.D., M.D., L.M., I.B., J.-P.F., I.d.W., P.B., X.D., M.-A.L.); Institut National de la Santé et de la Recherche Médicale, Unité Mixte de Recherche S775, Bases Moléculaires de la Réponse aux Xénobiotiques, Paris, France (F.D., M.D., L.M., J.-P.F., I.d.W., P.B., M.-A.L.); Institut National de la Santé et de la Recherche Médicale U705, Centre National de la Recherche Scientifique, Unité Mixte de Recherche 7157, Neuropsychopharmacologie des Addictions, Faculté de Pharmacie, Paris, France (S.D., X.D.); Institut National de la Santé et de la Recherche Médicale U679, Assistance-Publique des Hôpitaux de Paris, Raymond Escourolle Neuropathology Laboratory, Hopital de La Salpétrière, Université Pierre et Marie Curie, Paris, France (V.S., C.D.); Technologie Servier, Orléans, France (O.C.); Institut National de la Santé etdela Recherche Médicale U735, Centre Rene Huguenin, St. Cloud, France (I.B.); Department of Physiology and Pharmacology, Section of Pharmacogenetics, Karolinska Institutet, Stockholm, Sweden (M.I.-S.); and Assistance-Publique des Hôpitaux de Paris, Hôpital Européen Georges Pompidou, Service de Biochimie, Pharmacogénétique et Oncologie Moléculaire, Paris, France (P.B., M.-A.L.)

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.