Regiospecific expression of cytochrome P-450s and microsomal epoxide hydrolase in human brain tissue.
The central nervous system is an important potential target for certain environmental protoxins, but relatively little is known regarding brain-specific expression of biotransformation enzyme systems. We undertook the present study to identify regional and cellular expression patterns of individual cytochrome P-450 genes (CYP) and microsomal epoxide hydrolase (mEH) in human brain. Various regions of normal human brain were isolated and examined with respect to mRNA levels of CYP1A1, CYP1A2, CYP2E1, CPY3A, and mEH, using specific oligomer probes and reverse transcriptase-coupled polymerase chain reaction analysis. We also used immunohistochemical techniques, with antipeptide-derived antibodies, to identify specific cells from various regions of the human brain producing CYP1A1 and mEH protein. Relatively equivalent mRNA expression levels of mEH were detected in the cerebellum (C), frontal (F), occipital (O), pons (P), red nucleus (RN), and substantia nigra (SN) regions of brain. The mRNA expression patterns of CYP2E1 and CYP1A2 were similar; although detected in all brain regions examined, the RN and SN exhibited lower levels of CYP2E1 and CYP1A2 mRNA expression compared to other regions. In addition, regional differences in CYP3A and CYP1A1 mRNA expression also were observed, with the highest level of CYP3A mRNA present in the P region compared to the C, F, O, and RN, while no CYP3A mRNA was detected in the SN. CYP1A1 mRNA expression was evident in all brain regions, but the levels of CYP1A1 mRNA in the P and RN were lower than in the C, F, O, and SN. In all cases, the regional mRNA expression levels of these CYP and mEH mRNAs were less than the corresponding levels detected from the same individual's liver. CYP1A1 and mEH immunoreactivity was present in most neurons of the SN, RN, P, median raphae, locus ceruleus, inferior vestibular nucleus, dorsal motor nucleus of the vagus, and thalamus. Some but not all astrocytes within these regions also demonstrated 1A1 and mEH immunoreactivity. These results indicate that many neurons and astrocytes express mEH and CYP1A1 as well as other CYP genes, and suggest that localized biotransformation events within the certain central nervous system may account for toxicities initiated by exposure to certain environmental chemicals.
Farin
F M
FM
Department of Environmental Health, School of Public Health and Community Medicine, University of Washington, Seattle 98195.
Omiecinski
C J
CJ
D001483:Base Sequence; D015153:Blotting, Western; D001921:Brain / Q000201:enzymology*; D003577:Cytochrome P-450 Enzyme System / Q000235:genetics / Q000378:metabolism*; D004247:DNA / Q000096:biosynthesis; D004851:Epoxide Hydrolases / Q000235:genetics / Q000378:metabolism*; D015971:Gene Expression Regulation, Enzymologic; D006801:Humans; D007150:Immunohistochemistry; D008099:Liver / Q000201:enzymology; D008861:Microsomes / Q000201:enzymology; D008969:Molecular Sequence Data; D016133:Polymerase Chain Reaction; D012333:RNA, Messenger / Q000032:analysis; D012194:RNA-Directed DNA Polymerase / Q000378:metabolism
D012333:RNA, Messenger; D004247:DNA; D003577:Cytochrome P-450 Enzyme System; D012194:RNA-Directed DNA Polymerase; D004851:Epoxide Hydrolases