Abstract
Cytochrome P450 2E1 (CYP2E1), which inter alia is located in dopamine containing neurons in the substantia nigra, has been hypothesized to be of importance for the pathophysiology of Parkinson’s disease (PD), either by its production of reactive oxygen species (ROS) or by its capability to detoxify putative neurotoxins. Numerous polymorphisms in the coding and non-coding regions of the gene for this enzyme have been reported. Different variants may account for inter-individual differences in the activity of the enzyme or production of ROS. In this study, the CYP2E1 gene was examined in a control population (n = 272) and a population with PD (n = 347), using a tag-single nucleotide polymorphism (tSNP) approach founded on HapMap Data. Six tSNPs were used in the analysis and haplotype block data were obtained. In case of significance, the SNP was further examined regarding early/late age of disease onset and presence of relatives with PD. We found an association between allele and genotype frequencies of the C/G polymorphism at intron 7 (rs2070676) of this gene and PD (P value of 0.026 and 0.027, respectively). Furthermore, analysis of the rs2070676 polymorphism in subgroups of patients with age of disease onset higher than 50 years and those not having a relative with PD also demonstrated a significant difference with controls. This was seen in both genotype (corresponding to P value = 0.039 and 0.032) and allele (P = 0.027 and 0.017 respectively) frequency. As a representative of many polymorphisms or in possible linkage disequilibrium with other functional variants, it is possible that rs2070676 could influence the regulation of the enzyme. In conclusion, our results display an association between the rs2070676 polymorphism and PD. Additional investigations are needed to elucidate the importance of this polymorphism for the activity of CYP2E1 and PD susceptibility.
Similar content being viewed by others
References
Andersen JK (2000) What causes the build-up of ubiquitin-containing inclusions in Parkinson’s disease? Mech Ageing Dev 118(1–2):15–22
Bandmann O, Vaughan J, Holmans P, Marsden CD, Wood NW (1997) Association of slow acetylator genotype for N-acetyltransferase 2 with familial Parkinson’s disease. Lancet 350(9085):1136–1139
Brockmoller J, Cascorbi I, Kerb R, Roots I (1996) Combined analysis of inherited polymorphisms in arylamine N-acetyltransferase 2, glutathione S-transferases M1 and T1, microsomal epoxide hydrolase, and cytochrome P450 enzymes as modulators of bladder cancer risk. Cancer Res 56(17):3915–3925
Brzezinski MR, Boutelet-Bochan H, Person RE, Fantel AG, Juchau MR (1999) Catalytic activity and quantitation of cytochrome P-450 2E1 in prenatal human brain. J Pharmacol Exp Ther 289(3):1648–1653
Carriere V, Berthou F, Baird S, Belloc C, Beaune P, de Waziers I (1996) Human cytochrome P450 2E1 (CYP2E1): from genotype to phenotype. Pharmacogenetics 6(3):203–211
Daniel SE, Lees AJ (1993) Parkinson’s Disease Society Brain Bank, London: overview and research. J Neural Transm Suppl 39:165–172
Danko IM, Chaschin NA (2005) Association of CYP2E1 gene polymorphism with predisposition to cancer development. Exp Oncol 27(4):248–256
de Rijk MC, Tzourio C, Breteler MM, Dartigues JF, Amaducci L, Lopez-Pousa S, Manubens-Bertran JM, Alperovitch A, Rocca WA (1997) Prevalence of parkinsonism and Parkinson’s disease in Europe: the EUROPARKINSON Collaborative Study. European Community Concerted Action on the Epidemiology of Parkinson’s disease. J Neurol Neurosurg Psychiatry 62(1):10–15
de Rijk MC, Launer LJ, Berger K, Breteler MM, Dartigues JF, Baldereschi M, Fratiglioni L, Lobo A, Martinez-Lage J, Trenkwalder C, Hofman A (2000) Prevalence of Parkinson’s disease in Europe: a collaborative study of population-based cohorts. Neurologic Diseases in the Elderly Research Group. Neurology 54(11 Suppl 5):S21–S23
Fahn S (2003) Description of Parkinson’s disease as a clinical syndrome. Ann N Y Acad Sci 991:1–14
Fahn S, Cohen G (1992) The oxidant stress hypothesis in Parkinson’s disease: evidence supporting it. Ann Neurol 32(6):804–812
Fairbrother KS, Grove J, de Waziers I, Steimel DT, Day CP, Crespi CL, Daly AK (1998) Detection and characterization of novel polymorphisms in the CYP2E1 gene. Pharmacogenetics 8(6):543–552
Farin FM, Omiecinski CJ (1993) Regiospecific expression of cytochrome P-450s and microsomal epoxide hydrolase in human brain tissue. J Toxicol Environ Health 40(2–3):317–335
Gonzalez FJ (1988) The molecular biology of cytochrome P450s. Pharmacol Rev 40(4):243–288
Hansson T, Tindberg N, Ingelman-Sundberg M, Kohler C (1990) Regional distribution of ethanol-inducible cytochrome P450 IIE1 in the rat central nervous system. Neuroscience 34(2):451–463
Hu Y, Oscarson M, Johansson I, Yue QY, Dahl ML, Tabone M, Arinco S, Albano E, Ingelman-Sundberg M (1997) Genetic polymorphism of human CYP2E1: characterization of two variant alleles. Mol Pharmacol 51(3):370–376
Itoga S, Nomura F, Makino Y, Tomonaga T, Shimada H, Ochiai T, Iizasa T, Baba M, Fujisawa T, Harada S (2002) Tandem repeat polymorphism of the CYP2E1 gene: an association study with esophageal cancer and lung cancer. Alcohol Clin Exp Res 26(8 Suppl):15S–19S
Jenner P (2003) Oxidative stress in Parkinson’s disease. Ann Neurol 53(Suppl 3):S26–S36 (discussion S36–S28)
Joshi M, Tyndale RF (2006) Regional and cellular distribution of CYP2E1 in monkey brain and its induction by chronic nicotine. Neuropharmacology 50(5):568–575
Karuzina II, Archakov AI (1994) The oxidative inactivation of cytochrome P450 in monooxygenase reactions. Free Radic Biol Med 16(1):73–97
Krajinovic M, Sinnett H, Richer C, Labuda D, Sinnett D (2002) Role of NQO1, MPO and CYP2E1 genetic polymorphisms in the susceptibility to childhood acute lymphoblastic leukemia. Int J Cancer 97(2):230–236
Ladero JM, Agundez JA, Rodriguez-Lescure A, Diaz-Rubio M, Benitez J (1996) RsaI polymorphism at the cytochrome P4502E1 locus and risk of hepatocellular carcinoma. Gut 39(2):330–333
Liou HH, Tsai MC, Chen CJ, Jeng JS, Chang YC, Chen SY, Chen RC (1997) Environmental risk factors and Parkinson’s disease: a case–control study in Taiwan. Neurology 48(6):1583–1588
Lucas D, Ferrara R, Gonzalez E, Bodenez P, Albores A, Manno M, Berthou F (1999) Chlorzoxazone, a selective probe for phenotyping CYP2E1 in humans. Pharmacogenetics 9(3):377–388
McBride OW, Umeno M, Gelboin HV, Gonzalez FJ (1987) A Taq I polymorphism in the human P450IIE1 gene on chromosome 10 (CYP2E). Nucleic Acids Res 15(23):10071
Montoliu C, Sancho-Tello M, Azorin I, Burgal M, Valles S, Renau-Piqueras J, Guerri C (1995) Ethanol increases cytochrome P4502E1 and induces oxidative stress in astrocytes. J Neurochem 65(6):2561–2570
Nissbrandt H, Bergquist F, Jonason J, Engberg G (2001) Inhibition of cytochrome P450 2E1 induces an increase in extracellular dopamine in rat substantia nigra: a new metabolic pathway? Synapse 40(4):294–301
Pezzoli G, Antonini A, Barbieri S, Canesi M, Perbellini L, Zecchinelli A, Mariani CB, Bonetti A, Leenders KL (1995) n-Hexane-induced parkinsonism: pathogenetic hypotheses. Mov Disord 10(3):279–282
Pirmohamed M, Kitteringham NR, Quest LJ, Allott RL, Green VJ, Gilmore IT, Park BK (1995) Genetic polymorphism of cytochrome P4502E1 and risk of alcoholic liver disease in Caucasians. Pharmacogenetics 5(6):351–357
Riedl AG, Watts PM, Edwards RJ, Boobis AR, Jenner P, Marsden CD (1996) Selective localisation of P450 enzymes and NADPH-P450 oxidoreductase in rat basal ganglia using anti-peptide antisera. Brain Res 743(1–2):324–328
Riedl AG, Watts PM, Jenner P, Marsden CD (1998) P450 enzymes and Parkinson’s disease: the story so far. Mov Disord 13(2):212–220
Riedl AG, Watts PM, Brown CT, Jenner P (1999) P450 and heme oxygenase enzymes in the basal ganglia and their roles in Parkinson’s disease. Adv Neurol 80:271–286
Shahabi HN, Andersson DR, Nissbrandt H (2008) Cytochrome P450 2E1 in the substantia nigra: relevance for dopaminergic neurotransmission and free radical production. Synapse 62(5):379–388
Sian J, Gerlach M, Youdim MB, Riederer P (1999) Parkinson’s disease: a major hypokinetic basal ganglia disorder. J Neural Transm 106(5–6):443–476
Sohda T, Shimizu M, Kamimura S, Okumura M (1993) Immunohistochemical demonstration of ethanol-inducible P450 2E1 in rat brain. Alcohol Alcohol Suppl 1B:69–75
Solus JF, Arietta BJ, Harris JR, Sexton DP, Steward JQ, McMunn C, Ihrie P, Mehall JM, Edwards TL, Dawson EP (2004) Genetic variation in eleven phase I drug metabolism genes in an ethnically diverse population. Pharmacogenomics 5(7):895–931
Staudt H, Lichtenberger F, Ullrich V (1974) The role of NADH in uncoupled microsomal monoxygenations. Eur J Biochem 46(1):99–106
The International HapMap Project (2003) Nature 426(6968):789–796
Tindberg N, Baldwin HA, Cross AJ, Ingelman-Sundberg M (1996) Induction of cytochrome P450 2E1 expression in rat and gerbil astrocytes by inflammatory factors and ischemic injury. Mol Pharmacol 50(5):1065–1072
Umeno M, McBride OW, Yang CS, Gelboin HV, Gonzalez FJ (1988) Human ethanol-inducible P450IIE1: complete gene sequence, promoter characterization, chromosome mapping, and cDNA-directed expression. Biochemistry 27(25):9006–9013
Upadhya SC, Tirumalai PS, Boyd MR, Mori T, Ravindranath V (2000) Cytochrome P4502E (CYP2E) in brain: constitutive expression, induction by ethanol and localization by fluorescence in situ hybridization. Arch Biochem Biophys 373(1):23–34
Vaglini F, Pardini C, Viaggi C, Bartoli C, Dinucci D, Corsini GU (2004) Involvement of cytochrome P450 2E1 in the 1-methyl-4-phenyl-1, 2, 3, 6-tetrahydropyridine-induced mouse model of Parkinson’s disease. J Neurochem 91(2):285–298
Viaggi C, Pardini C, Vaglini F, Corsini GU (2006) Cytochrome P450 and Parkinson’s disease: protective role of neuronal CYP 2E1 from MPTP toxicity. J Neural Transm Suppl 70:173–176
Wang J, Liu Z, Chan P (2000) Lack of association between cytochrome P450 2E1 gene polymorphisms and Parkinson’s disease in a Chinese population. Mov Disord 15(6):1267–1269
Warner TT, Schapira AH (2003) Genetic and environmental factors in the cause of Parkinson’s disease. Ann Neurol 53(Suppl 3):S16–S23 (discussion S23–S15)
Watts PM, Riedl AG, Douek DC, Edwards RJ, Boobis AR, Jenner P, Marsden CD (1998) Co-localization of P450 enzymes in the rat substantia nigra with tyrosine hydroxylase. Neuroscience 86(2):511–519
Wilms H, Zecca L, Rosenstiel P, Sievers J, Deuschl G, Lucius R (2007) Inflammation in Parkinson’s diseases and other neurodegenerative diseases: cause and therapeutic implications. Curr Pharm Des 13(18):1925–1928
Wong NA, Rae F, Simpson KJ, Murray GD, Harrison DJ (2000) Genetic polymorphisms of cytochrome p4502E1 and susceptibility to alcoholic liver disease and hepatocellular carcinoma in a white population: a study and literature review, including meta-analysis. Mol Pathol 53(2):88–93
Wu X, Shi H, Jiang H, Kemp B, Hong WK, Delclos GL, Spitz MR (1997) Associations between cytochrome P4502E1 genotype, mutagen sensitivity, cigarette smoking and susceptibility to lung cancer. Carcinogenesis 18(5):967–973
Wu RM, Cheng CW, Chen KH, Shan DE, Kuo JW, Ho YF, Chern HD (2002) Genetic polymorphism of the CYP2E1 gene and susceptibility to Parkinson’s disease in Taiwanese. J Neural Transm 109(11):1403–1414
Yang M, Tsuang J, Yvonne Wan YJ (2007) A haplotype analysis of CYP2E1 polymorphisms in relation to alcoholic phenotypes in Mexican Americans. Alcohol Clin Exp Res 31(12):1991–2000
Acknowledgments
The study was supported by the Swedish Research Council, Åhlén’s Foundation, Swedish Parkinson Foundation, Swedish Brain Power Initiative, Swedish Brain Foundation, Hållstens Forskningsstiftelse, Björn Oscarssons stiftelse and Karolinska Institutet Funds.
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Niazi Shahabi, H., Westberg, L., Melke, J. et al. Cytochrome P450 2E1 gene polymorphisms/haplotypes and Parkinson’s disease in a Swedish population. J Neural Transm 116, 567–573 (2009). https://doi.org/10.1007/s00702-009-0221-1
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s00702-009-0221-1