Co-localization of P450 enzymes in the rat substantia nigra with tyrosine hydroxylase
Section snippets
Materials
All chemicals were obtained from Sigma (Sigma Chemical Co. Ltd, Dorset, U.K.) unless otherwise stated.
Animals
Adult male adult Wistar rats (n=24; 150–200 g, Bantin and Kingman, Hull, U.K.) were housed six to a cage and given free access to pelleted food (Special Diet Services, Witham, U.K.) and water. All animal experiments were carried out in strict accordance with the U.K. Animals (Scientific Procedures) Act, 1986 and associated guidelines.
Preparation of antibodies
Polyclonal rabbit anti-peptide antibodies directed against
Peroxidase immunohistochemistry
Liver sections, used as positive controls, produced immunoreactive centrilobular staining using antisera targeted against CYP1A2, CYP2B1/2, CYP2E1, CYP2C12, CYP2C13/2C6, CYP3A1, CYP3A2 and NADPH-P450 oxidoreductase. Antisera against CYP2D1 produced an intense uniform panlobular staining. No immunoreactivity to antisera against CYP1A1 or CYP2D4 was observed in liver sections. However, antisera against CYP1A1 stained the globus pallidus intensely, while antisera against CYP2D4 weakly stained
Discussion
This is the first comprehensive investigation of the expression of multiple P450 enzymes in the substantia nigra and also the first to use exclusively anti-peptide antisera. The antisera used were highly specific, as a result of using short synthetic peptide sequences unique to each P450 enzyme.[24]
CYP2E1 was previously reported in neurons in the rat substantia nigra but diffuse staining was also observed in the SNpr and in many other brain regions including cells identified as glia.[29]Others
Conclusion
The expression of CYP2E1 in nigral dopaminergic neurons in the rat raises important questions about its physiological function at this site and if expressed in humans, it could be involved in mechanisms of cell death including Parkinson's disease. The presence of CYP2E1 has been reported in the human brain, although there are no reports of it being found in the substantia nigra. CYP2E1 expression may vary between individuals, as a result of polymorphisms in CYP2E1 promoters. Clearly such
Acknowledgements
This work was supported by the Medical Research Council, the Wellcome Trust, the Parkinson's Disease Society and the National Parkinson Foundation, Miami, U.S.A.
References (65)
- et al.
Frequency of a specific cytochrome P4502D6B (CYP2D6B) mutant allele in clinically differentiated groups of patients with Parkinson's disease
Biochem. molec. Med.
(1995) - et al.
Induction of brain cytochrome P-450IIE1 by chronic ethanol treatment
Brain Res.
(1993) - et al.
Rat brain cytochromes P-450: catalytic, immunochemical properties and inducibility of multiple forms
Brain Res.
(1990) - et al.
Differential effect of chronic nicotine administration on brain cytochrome P4501A1/2 and P4502E1
Biochem. biophys. Res. Commun.
(1993) - et al.
Mutant debrisoquine hydroxylation genes in Parkinson's disease
Lancet
(1992) - et al.
Brain mitochondrial cytochromes P450: xenobiotic metabolism, presence of multiple forms and their selective inducibility
Archs Biochem. Biophys.
(1995) - et al.
Estradiol and testosterone in specific regions of the human female brain in different endocrine states
J. Steroid Biochem. molec. Biol.
(1995) - et al.
Substantia nigra dopamine neurons: alterations in basal discharge rates and autoreceptor sensitivity induced by estrogen
Neuropharmacology
(1983) - et al.
Distribution and induction of CYP3A1 and CYP3A2 in rat liver and extra-hepatic tissues
Biochem. Pharmac.
(1995) Effects of testosterone upon MPTP-induced neurotoxicity of the nigrostriatal dopaminergic system of C57/B1 mice
Brain Res.
(1996)
Anti-peptide antibodies in studies of cytochromes P450 IA
Meth. Enzym.
Identification of the epitope of an anti-peptide antibody which binds to CYP1A2 in many species including man
Biochem. Pharmac.
Short synthetic peptides exploited for reliable and specific targeting of antibodies to the C-termini of cytochrome P450 enzymes
Biochem. Pharmac.
Presence of sex difference of cytochrome P-450 in rat preoptic area and hypothalamus with reference to coexistence with oxytocin
Brain Res.
Regional distribution of ethanol-inducible cytochrome P450 IIE1 in the rat central nervous system
Neuroscience
Immunohistochemical localization of cytochrome P-450 in rat brain
Neuroscience
Ethanol metabolism and alcoholic liver disease
Essays Biochem.
Immunohistochemical localization of cytochrome P-450 in the rat brain
Neurosci. Lett.
Localization of NADPH cytochrome P450 oxidoreductase in rat brain by immunohistochemistry and in situ hybridization and a comparison with the distribution of neuronal NADPH-diaphorase staining
Neuroscience
Translational activation of ethanol-inducible cytochrome P450 (CYP2E1) by isoniazid
Eur. J. Pharmac.
NADPH cytochrome P-450 reductase in rat, mouse and human brain
Biochem. Pharmac.
Selective localization of P450 enzymes and NADPH-P450 oxidoreductase in rat basal ganglia using anti-peptide antisera
Brain Res.
Cytochrome P450 and NADPH cytochrome c reductase in rat brain formation of reactive catechol metabolites
Biochem. biophys. Res. Commun.
Steroid metabolism by constitutive cytochromes P450
J. Steroid Biochem. molec. Biol.
Enoxacin is an inducer of CYP1A2 in rat liver
Biochem. Pharmac.
Peroxidase activity of liver microsomal vitamin D 25-hydroxylase and cytochrome P4501A2 catalyses 25-hydroxylation of vitamin D3 and oxidation of dopamine to aminochrome
Biochem. molec. Med.
Debrisoquine hydroxylase gene polymorphism and susceptibility to Parkinson's disease
Lancet
The role of environmental toxins in the etiology of Parkinson's disease
Trends Neurosci.
Analysis of the expression and the first exon of aromatase mRNA in monkey brain
J. Steroid Biochem. molec. Biol.
Identification of cytochrome P450 2E1 in rat brain
Biochem. biophys. Res. Commun.
Mechanisms of joint neurotoxicity of n-hexane, methyl isobutylketone and O-ethyl-O-4-nitrophenyl phenylphosphophonothioate in hens
J. Pharmac. exp. Ther.
Molecular characterization of an arachidonic acid epoxygenase in rat brain astrocytes
Stroke
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