Xenobiotic-metabolizing enzymes and transporters in the normal human brain: regional and cellular mapping as a basis for putative roles in cerebral function.
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.
Dutheil
Fabien
F
Université Paris Descartes, Paris, France.
Dauchy
Sandrine
S
Diry
Monique
M
Sazdovitch
Véronique
V
Cloarec
Olivier
O
Mellottée
Lucille
L
Bièche
Ivan
I
Ingelman-Sundberg
Magnus
M
Flinois
Jean-Pierre
JP
de Waziers
Isabelle
I
Beaune
Philippe
P
Declèves
Xavier
X
Duyckaerts
Charles
C
Loriot
Marie-Anne
MA
D018528:ATP-Binding Cassette Transporters / Q000235:genetics / Q000378:metabolism*; D001921:Brain / Q000201:enzymology* / Q000378:metabolism; D000090702:Constitutive Androstane Receptor; D006801:Humans; D012333:RNA, Messenger / Q000378:metabolism; D018160:Receptors, Cytoplasmic and Nuclear / Q000235:genetics / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction
D018528:ATP-Binding Cassette Transporters; D000090702:Constitutive Androstane Receptor; C000716327:NR1I3 protein, human; D012333:RNA, Messenger; D018160:Receptors, Cytoplasmic and Nuclear