title: Subcellular localization of cytochrome P450, and activities of several enzymes responsible for drug metabolism in the human brain.
abstract: We studied the subcellular distribution of cytochrome P450 and related monooxygenase activities in six regions of human brains removed at autopsy. The content of total cytochrome P450 was found to be at least nine times higher in the mitochondrial fraction than in the microsomes in all the regions studied. However, cytochrome P450-dependent enzymatic activities which are representative of different isoforms metabolizing exogenous molecules exhibited a microsomal prevalence, a situation previously observed in rat brain. The other drug-metabolizing enzymes catalysing functionalization and conjugation reactions, presented the following characteristics in human brain: (i) a low activity of NADPH-cytochrome P450 reductase, which also catalyses the reduction of some xenobiotics; (ii) a high specific activity of the membrane-bound epoxide hydrolase; (iii) among the enzymes catalysing conjugation reactions, 1-naphthol-UDP-glucuronosyltransferase activity was barely or not detectable, whereas the mean glutathione-S-transferase activity was 15 times higher than the activity measured in rat brain. The presence of several drug-metabolizing enzyme activities in human brain microvessels, and particularly the high activity of epoxide hydrolase, suggests a participation of these enzymes in the metabolic blood-brain barrier.
authors.affiliation: Centre du Médicament, Université de Nancy I, CNRS URA 597, France.
authors.forename: J F
authors.initials: JF
authors.lastname: Ghersi-Egea
authors.forename: R
authors.initials: R
authors.lastname: Perrin
authors.forename: B
authors.initials: B
authors.lastname: Leininger-Muller
authors.forename: M C
authors.initials: MC
authors.lastname: Grassiot
authors.forename: C
authors.initials: C
authors.lastname: Jeandel
authors.forename: J
authors.initials: J
authors.lastname: Floquet
authors.forename: G
authors.initials: G
authors.lastname: Cuny
authors.forename: G
authors.initials: G
authors.lastname: Siest
authors.forename: A
authors.initials: A
authors.lastname: Minn
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D000818:Animals; D001923:Brain Chemistry; D002540:Cerebral Cortex / Q000098:blood supply / Q000201:enzymology; D019363:Cytochrome P-450 CYP1A1; D019362:Cytochrome P-450 CYP2B1; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism*; D004851:Epoxide Hydrolases / Q000378:metabolism; D005260:Female; D005982:Glutathione Transferase / Q000378:metabolism; D006801:Humans; D008658:Inactivation, Metabolic; D008297:Male; D008875:Middle Aged; D008995:Monoamine Oxidase / Q000378:metabolism; D009251:NADPH-Ferrihemoprotein Reductase / Q000378:metabolism; D010088:Oxidoreductases / Q000378:metabolism; D004364:Pharmaceutical Preparations / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D013048:Specimen Handling; D013347:Subcellular Fractions / Q000201:enzymology / Q000648:ultrastructure
chemical_list: D004364:Pharmaceutical Preparations; D003577:Cytochrome P-450 Enzyme System; D010088:Oxidoreductases; D019363:Cytochrome P-450 CYP1A1; D019362:Cytochrome P-450 CYP2B1; D008995:Monoamine Oxidase; D009251:NADPH-Ferrihemoprotein Reductase; D005982:Glutathione Transferase; D004851:Epoxide Hydrolases