Regional and cellular expression of CYP2D6 in human brain: Higher levels in alcoholics

Journal of Neurochemistry

Volumn 82, Issue 6, 2002, Pages 1376-1387

  Miksys, Sharon ^a   Rao, Yushu ^a   Hoffmann, Ewa ^a   Mash, Deborah C ^b   Tyndale, Rachel F ^a,c  

^a UNIVERSITY OF TORONTO   (Canada)

^b UNIVERSITY OF MIAMI MILLER SCHOOL OF MEDICINE   (United States)

^c UNIVERSITY OF TORONTO   (Canada)

Author keywords

Alcoholism; Cytochrome P450 CYP2D6; Drug metabolism; Human brain; Neurotoxicity

Indexed keywords

CYTOCHROME P450 2D6; MESSENGER RNA;

ADULT; ALCOHOLISM; ARTICLE; BEHAVIOR; BRAIN; CEREBELLUM; CLINICAL ARTICLE; CONTROLLED STUDY; DENTATE GYRUS; DRUG METABOLISM; ENZYME LOCALIZATION; GENOTYPE; GRANULAR CELL; HUMAN; HUMAN TISSUE; IMMUNOBLOTTING; IMMUNOCYTOCHEMISTRY; NEUROTOXICITY; PRIORITY JOURNAL; PROTEIN EXPRESSION; PURKINJE CELL; PYRAMIDAL NERVE CELL; REVERSE TRANSCRIPTION POLYMERASE CHAIN REACTION; SOUTHERN BLOTTING;

ADULT; AGED; ALCOHOLISM; ANTIBODY SPECIFICITY; BLOTTING, SOUTHERN; BRAIN; BRAIN CHEMISTRY; CEREBELLUM; CYTOCHROME P-450 CYP2D6; FRONTAL LOBE; GENOTYPE; HIPPOCAMPUS; HUMANS; IMMUNOBLOTTING; IMMUNOHISTOCHEMISTRY; MIDDLE AGED; NEURONS; ORGAN SPECIFICITY; PURKINJE CELLS; PYRAMIDAL CELLS; RNA, MESSENGER; SMOKING;

EID: 0036736195     PISSN: 00223042     EISSN: None     Source Type: Journal    
DOI: 10.1046/j.1471-4159.2002.01069.x     Document Type: Article

References (87)

1. Baum L. O. and Strobel H. W. (1997) Regulation of expression of cytochrome P-450 2D mRNA in rat brain with steroid hormones. Brain Res. 765, 67-73.
2. Bellis M. D. D., Clark D. B., Beers S. R., Soloff P. H., Boring A. M., Hall J., Kersh A. and Keshavan M. S. (2000) Hippocampal volume in adolescent-onset alcohol use disorders. Am. J. Psychiatry 157, 737-744.
3. Bhagwat S. V., Boyd M. R. and Ravindranath V. (1995) Brain mitochondrial cytochromes P450: xenobiotic metabolism, presence of multiple forms and their selective inducibility. Arch. Biochem. Biophys. 320, 73-83.
4. Boopathi E., Anandatheerthavarada H. K., Bhagwat S. V., Biswas G., Fang J.-K. and Avadhani N. G. (2000) Accumulation of mitochondrial P450MT2, NH2-terminal truncated cytochrome P4501A1 in rat brain during chronic treatment with β-naphthoflavone. J. Biol. Chem. 275, 34415-34423.
5. Boustead C., Taber H., Idle J. R. and Cholerton S. (1997) CYP2D6 genotype and smoking behaviour in cigarette smokers. Pharmacogenetics 7, 411-414.
6. Bradford M. M. (1976) A rapid and sensitive method for the quantification of microgram quantities of protein utilizing the principle of protein-dye binding. Anal. Biochem. 72, 248-254.
7. Castagnoli N. Jr, Rimoldi J. M., Bloomquist J. and Castagnoli K. P. (1997) Potential metabolic bioactivation pathways involving cyclic tertiary amines and azaarenes. Chem. Res. Toxicol. 10, 924-940.
8. Chen Z. R., Irvine R. J., Bodiner F. and Somogy A. A. (1990) Morphine formation from codeine in rat brain: a possible mechanism of codeine analgesia. Life Sci. 46, 1067-1074.
9. Chu T., Kumagai Y., DiStefano E. W. and Cho A. K. (1996) Disposition of methylenedioxymethamphetamine and three metabolites in the brains of different rat strains and their possible roles in acute serotonin depletion. Biochem. Pharmacol. 51, 789-796.
10. Coleman T., Spellman E. F., Rostami-Hodjegan A., Lennard M. S. and Tucker G. T. (2000) The 1′-hydroxylation of Rac-bufuralol by rat brain microsomes. Drug Metab. Dispos. 28, 1094-1099.
11. Cribb A., Nuss C. and Wang R. (1995) Antipeptide antibodies against overlapping sequences differentially inhibit human CYP2D6. Drug Metab. Dispos. 23, 671-675.
12. Donnerer J., Oka K., Brossi A., Rice K. C. and Spector S. (1986) Presence and formation of codeine and morphine in the rat. Proc. Natl Acad. Sci. USA 83, 4566-4567.
13. Elexpuru-Camiruaga J., Buxton N., Kandula V., Dias P. S., Campbell D., McIntosh J., Broome J., Jones P., Inskip A. and Alldersea J. (1995) Susceptibility to astrocytoma and meningioma: influence of allelism at glutathione S-transferase (GSTT1 and GSTM1) and cytochrome P-450 (CYP2D6) loci. Cancer Res. 55, 4237-4239.
14. Faraj B. A., Davis D. C., Camp V. M., Mooney A. J. III and Holloway T. (1994) The effect of cocaine abuse on plasma levels of sulfated dopamine and salsolinol in alcoholics. Alcohol 11, 337-342.
15. Gaedigk A., Gotschall R. R., Forbes N. S., Simon S. D., Kearns G. L. and Leeder J. S. (1999) Optimization of cytochrome P4502D6 (CYP2D6) phenotype assignment using a genotyping algorithm based on allelic frequency data. Pharmacogenetics 9, 669-682.
16. Ghersi-Egea J.-F., Perrin R., Leninger-Mueller B., Grassiot M.-C., Jeandel C., Floquet J., Cuny G., Siest G. and Minn A. (1993) Subcellular localization of cytochrome P450 and activities of several enzymes responsible for drug metabolism in the human brain. Biochem. Pharmacol. 45, 647-658.
17. Gilham D. E., Cairns W., Paine M. J. I., Modi S., Poulsom R., Roberts G. C. K. and Wolf C. R. (1997) Metabolism of MPTP by cytochrome P4502D6 and the demonstration of 2D6 mRNA in human foetal and adult brain by in situ hybridization. Xenobiotica 27, 111-125.
18. Gonzalez F. J., Skoda R. C., Kimura S., Umeno M., Zanger U. M., Nebert D. W., Gelboin H. V., Hardwick J. P. and Meyer U. A. (1988) Characterization of the common genetic defect in humans deficient in debrisoquine metabolism. Nature 331, 442-446.
19. Gough A. C., Miles J. S., Spurr M. K., Moss J. E., Gaedigk A., Eichelbaum M. and Wolf C. R. (1990) Identification of the primary gene defect at the cytochrome P450 CYP2D locus. Nature 347, 773-776.
20. Hanioka N., Kimura S., Meyer U. A. and Gonzalez F. J. (1990) The human CYP2D locus associated with a common genetic defect in drug oxidation: a G1934 to A base change in intron 3 of a mutant CYP2D6 allele results in an aberrant 3′ splice recognition site. Am. J. Hum. Genet. 47, 994-1001.
21. Hedlund E., Wyss A., Kainu T., Backlund M., Kohler C., Pelto-Hiukko M., Gustafsson J. A. and Warner M. (1996) Cytochrome P4502D4 in the brain: specific neuronal regulation by clozapine and toluene. Mol. Pharmacol. 50, 342-350.
22. Heim M. and Meyer U. A. (1990) Genotyping of poor metabolizers of debrisoquine by allele-specific PCR amplification. Lancet 336, 529-532.
23. Heim M. H. and Meyer U. A. (1992) Evolution of a highly polymorphic human cytochrome P450 gene cluster: CYP2D6. Genomics 14, 49-58.
24. Herz A. (1997) Endogenous opioid systems and alcohol addiction. Psychopharmacology (Berl.) 129, 99-111.
25. Hiroi T., Imaoka S. and Funae Y. (1998) Dopamine formation from tyramine by CYP2D6. Biochem. Biophys. Res. Commun. 249, 838-843.
26. Honkakoski P., Kojo A., Raunio H., Pasanen M., Juvonen R. and Lang M. A. (1988) Hepatic mitochondrial coumarin 7-hydroxylase: comparison with the microsomal enzyme. Arch. Biochem. Biophys. 267, 558-567.
27. Irle E. and Markowitsch H. J. (1983) Widespread neuroanatomical damage and learning deficits following chronic alcohol consumption or vitamin-B1 (thiamine) deficiency in rats. Behav. Brain Res. 9, 277-294.
28. Jolivalt C., Minn A., Vincent-Viry M., Galteau M.-M. and Siest G. (1995) Dextromethorphan O-demethylase activity in rat brain microsomes. Neurosci. Lett. 187, 65-68.
29. Kalow W. and Tyndale R. F. (1992) Debrisoquine.sparteine monooxygenase and other P-450s in brain, in Pharmacogenetics of Drug Metabolism (Kalow W., ed.), pp. 649-656. Pergamon Press, New York.
30. Kimura S., Umeno M., Skoda R. C., Meyer U. A. and Gonzalez F. J. (1989) The human debrisoquine 4-hydroxylase (CYP2D) locus: sequence and identification of the polymorphic CYP2D6 gene, a related gene, and a pseudogene. Am. J. Hum. Genet. 45, 889-904.
31. Krishna D. R. and Klotz U. (1994) Extrahepatic metabolism of drugs in humans. Clin. Pharmacokinet 26, 144-160.
32. Laakso M. P., Vaurio O., Savolainen L., Repo E., Soininen H., Aronen H. J. and Tiihonen J. (2000) A volume tric MRI study of the hippocampus in type 1 and 2 alcoholism. Behav. Brain Res. 109, 177-186.
33. Lieber C. S. (1999) Microsomal ethanol-oxidizing system (MEOS); the first 30 years (1968-98) - a review. Alcohol Clin. Exp. Res. 23, 991-1007.
34. Llerena A., Cobaleda J., Martinez C. and Benitez J. (1996) Interethnic differences in drug metabolism: influence of genetic and environmental factors on debrisoquine hydroxylation phenotype. Eur. J. Drug Metab. Pharmacokinet. 21, 129-138.
35. Loeper J., Descatoire V., Maurice M., Beaune P., Feldmann G., Larrey D. and Pessayre D. (1990) Presence of functional cytochrome P-450 on isolated rat hepatocyte plasma membrane. Hepatology 11, 850-858.
36. Loeper J., Louerat-Oriou B., Duport C. and Pompon D. (1998) Yeast expressed cytochrome P450 2D6 (CYP2D6) exposed on the external face of plasma membrane is functionally competent. Mol. Pharmacol. 54, 8-13.
37. Lundqvist C., Alling C., Knoth R. and Volk B. (1995) Intermittent ethanol exposure of adult rats: hippocampal cell loss after one month of treatment. Alcohol 30, 737-748.
38. McFadyen M. C. E., Melvin W. T. and Murray G. I. (1998) Regional distribution of individual forms of cytochrome P450 mRNA in normal adult human brain. Biochem. Pharmacol. 55, 825-830.
39. Meyer U. A., Skoda R. C. and Zanger U. M. (1990) The genetic polymorphism of debrisoquine/sparteine metabolism - molecular mechanisms. Pharmacol. Ther. 46, 297-308.
40. Michels R. and Marzuk P. M. (1993) Medical progress: progress in psychiatry (first of two parts). N. Engl. J. Med. 329, 552-560.
41. Miksys S., Hoffmann E. and Tyndale R. F. (2000a) Regional and cellular induction of nicotine-metabolizing CYP2B1 in rat brain by chronic nicotine treatment. Biochem. Pharmacol. 59, 1501-1511.
42. Miksys S., Rao Y. M., Sellers E., Kwan M., Mendis D. and Tyndale R. (2000b) Regional and cellular distribution of CYP2D subfamily members in rat brain. Xenobiotica 30, 547-564.
43. Miksys S. L., Schoedel K. A., Mash D. C. and Tyndale R. F. (2001) Nicotine-metabolizing CYP2B6 enzyme in human brain regions: higher levels in smokers and smoking alcoholics. FASEB 15, A573.
44. Mikus G., Somogyi A. A., Bochner F. and Eichelbaum M. (1991) Thebaine O-demethylation to oripavine: genetic differences between two rat strains. Xenobiotica 21, 1501-1509.
45. Montoliu C., Valles S., Renau-Piqueras J. and Guerri C. (1994) Ethanol-induced oxygen radical formation and lipid peroxidation in rat brain: effect of chronic alcohol consumption. J. Neurochem. 63, 1855-1862.
46. Mortimer O., Persson K., Ladona G., Spalding D., Zanger U. M., Meyer U. A. and Rane A. (1990) Polymorphic formation of morphine from codeine in poor and extensive metabolizers of dextromethorphan: relationship to the presence of immunoidentified cytochrome P-450IID1. Clin. Pharmacol. Ther 47, 27-35.
47. Myers R. D. and Melchior C. L. (1977) Differential actions on voluntary alcohol intake of tetrahydoisoquinolines or a beta-carboline infused chronically in the ventricle of the rat. Pharmacol. Biochem. Behav. 7, 381-392.
48. Myers R. D. and Privett T. H. (1989) A neuroanatomical substrate for alcohol drinking: identification of tetrahydropapaveroline (THP)-reactive sites in the rat brain. Brain Res. Bull. 22, 899-911.
49. Nebert D. W., Nelson R., Coon M. J., Estabrook W. W., Feyereisen R., Fujii-Kuriyama Y., Gonzalez F. J., Guengerich F. P., Gunsalus I. C., Johnson E. F., Loper J. C., Sato R., Waterman M. R. and Wasman D. J. (1991) The P450 superfamily: update on new sequences, gene mapping, and recommended nomenclature. DNA Cell Biol. 10, 1-14.
50. Neve E. P. A., Eliasson E., Pronzato M. A., Albano E., Marinari U. and Ingelman-Sundberg M. (1996) Enzyme-specific transport of rat liver cytochrome P450 to the Golgi apparatus. Arch. Biochem. Biophys. 333, 459-465.
51. 3H]GBR-12935 binding proteins. Arch. Biochem. Biophys. 276, 424-432.
52. Norris P. J., Hardwick J. P. and Emson P. C. (1996) Regional distribution of cytochrome P450 2D1 in the rat central nervous system. J. Comp. Neurol. 366, 244-258.
53. Ohmori O., Suzuki T., Kojima H., Shinkai T., Terao T., Mita T. and Abe K. (1998) Tardive dyskinesia and debrisoquine 4-hydroxylase (CYP2D6) genotype in Japanese schizophrenics. Schizophr Res. 32, 107-113.
54. Parkinson A. (1996) Biotransformation of xenobiotics, in Casarett and Doull's Toxicology; the Basic Science of Poisons (Klasson C. D., ed.), pp. 113-185. Mcgraw-Hill, New York
55. McGraw-Hill, New York. Patten C. J., Smith T. J., Murphy S. E., Wang M.-H., Lee J., Tynes R. E., Koch P. and Yang C. S. (1996) Kinetic analysis of the activation of 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone by heterologously expressed human P450 enzymes and the effect of P450-specific chemical inhibitors on this activation in human liver microsomes. Arch. Biochem. Biophys. 333, 127-138.
56. Pentney R. J. and Quackenbush L. J. (1990) Dendritic hypertrophy in Purkinje neurons of old Fischer 344 rats after long-term ethanol treatment. Alcohol Clin. Exp. Res. 14, 878-886.
57. Phillips S. C. (1990) Cerebellar white matter after long-term ethanol consumption in mice. J. Stud. Alcohol 51, 14-18.
58. Pomerleau O. F. (1998) Endogenous opioids and smoking: a review of progress and problems. Psychoneuroendocrinology 23, 115-130.
59. Ramamoorthy Y., Tyndale R. F. and Sellers E. M. (2001) Cytochrome P450 2D6.1 and cytochrome P450 2D6.10 differ in catalytic activity for multiple substrates. Pharmacogenetics 11, 477-487.
60. Ravindranath V. (1998) Metabolism of xenobiotics in the central nervous system implications and challenges. Biochem. Pharmacol. 56, 547-551.
61. Riedl A. G., Watts P. M., Jenner P. and Marsden C. D. (1998) P450 enzymes and Parkinson's disease: the story so far. Mov. Disord. 13, 212-220.
62. Riedl A. G., Watts P. M., Edwards R. J., Schulz-Utermoehl T., Boobis A. R., Jenner P. and Marsden C. K. (1999) Expression and localization of CYP2D enzymes in rat basal ganglia. Brain Res. 822, 175-191.
63. Riley J. N. and Walker D. W. (1978) Morphological alterations in hippocampus after long-term alcohol consumption in mice. Science 201, 646-648.
64. Robin M. A., Maratrat M., Loeper J., Durand-Schneider A. M., Tinel M., Ballet F., Beaune P., Feldmann G. and Pessayre D. (1995) Cytochrome P4502B follows a vesicular route to the plasma membrane in cultured rat hepatocytes. Gastroenterology 108, 1110-1123.
65. Robin M., LeRoy M., Descatoire V. and Pessayre D. (1997) Plasma membrane cytochromes P450 as neoantigens and autoimmune targets in drug-induced hepatitis. J. Hepatol. 26, 23-30.
66. Saarikoski S. T., Sata F., Husgafvel-Pursiainen K., Rautalahti M., Haukka J., Impivaara O., Jarvisalo J., Vainio H. and Hirvonen A. (2000) CYP2D6 ultrarapid metabolizer genotype as a potential modifier of smoking behaviour. Pharmacogenetics 10, 5-10.
67. Schoedel K. A., Sellers E. M. and Tyndale R. F. (2001) Induction of CYP2B1/2 and nicotine metabolism by ethanol in rat liver but not rat brain. Biochem. Pharmacol. 62, 1025-1036.
68. Siegle I., Fritz P., Eckhardt K., Zanger U. M. and Eichelbaum M. (2001) Cellular localization and regional distribution of CYP2D6 mRNA and protein expression in human brain. Pharmacogenetics 11, 237-245.
69. Strobel H. W., Kawashima H., Geng J., Sequieira D., Bergh A., Hodgson A. V., Wang H. and Shen S. (1995) Expression of multiple forms of brain cytochrome P450. Toxicol. Lett. 82/83, 639-643.
70. Suzuki T., Fujita S., Narimatsu S., Masubuchi Y., Tachibana M., Ohta S. and Hirobe M. (1992) Cytochrome P450 isozymes catalyzing 4-hydroxylation of parkinsonism-related compound 1,2,3,4-tetra-hydroisoquinoline in rat liver microsomes. FASEB 6, 771-776.
71. Tanaka S., Chen X., Xia Y., Kang D. E., Matoh N., Sundsmo M., Thomas R. G., Katzman R., Thal L. J., Trojanowski J. Q., Saitoh T., Ueda K. and Masliah E. (1998) Association of CYP2D microsatellit polymophism with Lewy body variant of Alzheimer's disease. Neurology 50, 1556-1562.
72. Tauer U., Knoth R. and Volk B. (1998) Phenytoin alters Purkinje cell axon morphology and targeting in vitro. Acta Neuropathol. 95, 583-591.
73. Thomas J. D., Goodlett C. R. and West J. R. (1998) Alcohol-induced Purkinje cell loss depends on developmental timing of alcohol exposure and correlates with motor performance. Brain Res. Dev. Brain Res. 105, 159-166.
74. Tyndale R. F., Sunahara R., Inaba T., Kalow W., Gonzalez F. J. and Niznik H. B. (1991) Neuronal cytochrome P450IID1 (debrisoquine/sparteine-type): potent inhibition of activity by (-)-cocaine and nucleotide sequence identity to human hepatic P450 gene: CYP2D6. Mol. Pharmacol. 40, 63-68.
75. Tyndale R. F., Li Y., Li N.-Y., Messina E., Miksys S. and Sellers E. M. (1999) Characterization of cytochrome P-450 2D1 activity in rat brain: high-affinity kinetics for dextromethorphan. Drug Metab. Dispos. 27, 924-930.
76. Uzbay I. T., Usanmaz S. E. and Akarsu E. S. (2000) Effects of chronic ethanol administration on serotonin metabolism in the various regions of the rat brain. Neurochem. Res. 25, 257-262.
77. Uzbay I. T., Usanmaz S. E., Tapanyigit E. E., Aynacioglu S. and Akarsu E. S. (1998) Dopaminergic and serotoninergic alterations in the rat brain during ethanol withdrawal: association with behavioral signs. Drug Alcohol Depend. 53, 39-47.
78. Vincent-Viry M., Fournier B. and Galteau M.-M. (2000) The effects of drinking and smoking on the CYP2D6 metabolic capacity. Drug Metab. Dispos. 28, 617-619.
79. Voirol P., Jonzier-Perey M., Porchet F., Reymond M. J., Janzer R. C., Bouras C., Strobel H. W., Kosel M., Eap C. B. and Baumann P. (2000) Cytochrome P-450 activities in human and rat brain microsomes. Brain Res. 855, 235-243.
80. Volk B., Hettmannsperger U., Papp T., Amelizad Z., Oesch F. and Knoth R. (1991) Mapping of phenytoin-inducible cytochrome P450 immunoreactivity in the mouse central nervous system. Neuroscience 42, 215-235.
81. Wadelius M., Darj E., Frenne G. and Rane A. (1997) Induction of CYP2D6 in pregnancy. Clin. Pharmacol. Ther. 62, 400-407.
82. Walther B., Ghersi-Egea J. F., Minn A. and Siest G. (1986) Subcellular distribution of cytochrome P-450 in the brain. Brain Res. 375, 338-344.
83. Warner M. and Gustafsson J. A. (1994) Effect of ethanol on cytochrome P450 in the rat brain. Proc. Natl Acad. Sci. USA 91, 1019-1023.
84. Weitz C. J., Faull K. F. and Goldstein A. (1987) Synthesis of the skeleton of the morphine molecule by mammalian liver. Nature 330, 674-677.
85. Wu D. and Cederbaum A. I. (1992) Presence of functionally active cytochrome P-450IIE1 in the plasma membrane of rat hepatocytes. Hepatology 15, 515-524.
86. Wundrack I., Meese E., Mullenbach R. and Blin N. (1994) Debrisoquine hydroxylase gene polymorphism in meningioma. Acta Neuropathol. (Berlin) 88, 472-474.
87. Xie W. and Rothblum L. I. (1991) Rapid, small-scale RNA isolation from tissue culture cells. Biotechniques 11, 325-327.