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Expression of constitutive and inducible cytochrome P450 2E1 in rat brain

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Abstract

Studies initiated to investigate the expression of cytochrome P450 2E1 (CYP2E1) in rat brain demonstrated low but detectable protein and mRNA expression in control rat brain. Though mRNA and protein expression of CYP2E1 in brain was several fold lower as compared to liver, relatively high activity of N-nitrosodimethylamine demethylase (NDMA-d) was observed in control rat brain microsomes. Like liver, pretreatment with CYP2E1 inducers such as ethanol or pyrazole or acetone significantly increased the activity of brain microsomal NDMA-d. Kinetic studies also showed an increase in the Vmax and affinity (Km) of the substrate towards the brain enzyme due to increased expression of CYP2E1 in microsomes of brain isolated from ethanol pretreated rats. In vitrostudies using organic inhibitors, specific for CYP2E1 and anti-CYP2E1 significantly inhibited the brain NDMA-d activity indicating that like liver, NDMA-d activity in rat brain is catalyzed by CYP2E1. Olfactory lobes exhibited the highest CYP2E1 expression and catalytic activity in control rats. Furthermore, several fold increase in the mRNA expression and activity of CYP2E1 in cerebellum and hippocampus while a relatively small increase in the olfactory lobes and no significant change in other brain regions following ethanol pretreatment have indicated that CYP2E1 induction maybe involved in selective sensitivity of these brain areas to ethanol induced free radical damage and neuronal degeneration.

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References

  1. Gonzalez FJ, Skoda RC, Kimura S, Umeno M, Zanger UM, Nebert DW, Gelboin HV, Hardwick JP, Meyer UA: Molecular characterization of the common human deficiency in metabolism of debrisoquine and other drugs. Nature 331:442–446, 1990

    Article  Google Scholar 

  2. Guengerich FP, Shimada T: Oxidation of toxic and carcinogenic chemicals by human cytochrome P450 enzymes. Chem. Res. Toxicol 4: 391–407,1991

    Article  PubMed  CAS  Google Scholar 

  3. Murray GI, Burke MD: Immunohistochemistry of drug—metabolizingenzymes. Biochem, Pharm 50: 895–903, 1995

    Article  CAS  Google Scholar 

  4. Philpot RM: Characterization of cytochrome P450 in extrahepatic tissues. Methods in Enzymology 206: 623–31, 1991

    Article  PubMed  CAS  Google Scholar 

  5. Das M, Seth PK, Mukhtar H: Characterization of microsomal aryl hydrocarbon hydroxylase of rat brain. Pharmacol J, Exp. Ther. 216: 156–161,1981

    CAS  Google Scholar 

  6. Dhawan A, Parmar D, Dayal M, Seth PK: Cytochrome P450 (P450)isoenzyme specific dealkylation of alkoxyresorufins in rat brain microsomes. Mol. Cell. Biochem 200: 169–176, 1999

    Article  PubMed  CAS  Google Scholar 

  7. Parmar D, Dhawan A, Seth, PK: Evidence for dealkylation of 7-pentoxyresorufin by cytochrome P450 2B1/2B2 isoenzymes in brain. Mol.Cell. Biochem 189: 201–205, 1998a

    Article  CAS  Google Scholar 

  8. Parmar D, Dhawan A, Seth PK: Immunochemical evidence for the presence of Phenobarbital (PB) and 3-methylcholanthrene (MC) inducible cytochromeP450 isoenzymes in rat brain. Int J, Toxicol. 17: 619–630, 1998b

    Article  CAS  Google Scholar 

  9. Ravindranath, Anandatheerthavarada HK: High activity of cytochrome P—450 linked aminopyrene N-demethylase in mouse brain microsomes andassociated sex related differences. Biochem J 261: 769–773, 1989

    PubMed  CAS  Google Scholar 

  10. Strobel HW, Kawashima H, Geng J, Sequeira D, Bergh A, Hodgson AV, Wang H, Shen S: Expression of multiple forms of brain cytochrome P450. Toxicology Letters 82–83: 639–643, 1995

    Article  PubMed  Google Scholar 

  11. Lieber CS: Cytochrome P4502E1: its physiological, pathological role.Physiol. Rev. 77: 517–544, 1997

    PubMed  CAS  Google Scholar 

  12. Raucy JL: Risk assessment: toxicity from chemical exposure resulting from enhanced expression of CYP 2E1, Toxicology 105: 217–223, 1995

    Article  PubMed  CAS  Google Scholar 

  13. Ekstorm G, Ingelman—Sundberg M: Rat liver Microsomal NADPH supported oxidase activity and lipid peroxidation dependent on ethanol—induciblecytochrome P450. Biochem, Pharmacol 38: 1313–1319, 1989

    Article  Google Scholar 

  14. Okhuwa T, Sato Y, Naoi M: Hydroxyl radical formation in diabeticrats induced by streptozotocin. Life Sci. 56: 1789–1798, 1995

    Article  Google Scholar 

  15. Ronis M JJ, Huang J, Crouch J, Mercado C, Irby D, Valentin CR, Lumpkin CK, Ingelman—Sundberg M., Badger TM: Cytochrome P450 CYP 2E1 induction during chronic alcohol exposure occurs by a two step mechanism associated with blood alcohol concentration in rats. J. Pharmacol. Exp. Ther. 264:944–950, 1993

    PubMed  CAS  Google Scholar 

  16. Hong J, Pan J, Gonzalez FJ, Gelboin HV, Yang CS: The induction of a specific form of cytochrome P450 (P450j) by fasting. Biophys. Res. Commun.142: 1077–1083, 1987

    Article  CAS  Google Scholar 

  17. Kimberley JW, Hafner MS, Novak RF: Insulin signaling in the transcriptional and posttranscriptional regulation of CYP2E1 expression.Hepatology 35: 263–273, 2002

    Article  CAS  Google Scholar 

  18. Ingelman—Sundberg M, Johansson I, Hu Y, Tereliees Y, Eliasson E, Clot P, Albano E: Ethanol inducible cytochrome P450 2E1: Genetic polymorphism, regulation and possible role in the etiology of alcohol induced liverdisease. Alcohol 16: 447–452, 1993

    Article  Google Scholar 

  19. French SW: Rationale for therapy for alcoholic liver disease.Gasteroenterology 109: 617–620, 1995

    Article  CAS  Google Scholar 

  20. Roberts BJ, Shof SE, Jeong KS, Song BJ: Induction of CYP2E1 in liver, kidney, brain and intestine during chronic ethanol administration andwithdrawal: evidence that CYP2E1 possesses a rapid phase half-life of 6 h or less. Biochem. Biophys. Res. Commun 205: 1064–1071, 1994

    Article  PubMed  CAS  Google Scholar 

  21. Warner M, Gustafsson JA: Effect of ethanol inducible cytochrome P450 in the rat brain. Proc. Natl. Acad. Sci. USA 91: 1019–1023, 1994

    Article  PubMed  CAS  Google Scholar 

  22. Tindberg N, Ingelman-Sundberg M: Expression, catalytic activity, and inducibility of cytochrome P450 2EI (CYP 2EI) in the rat central nervoussystem. J Neurochem 67: 2066–2073, 1996

    Article  PubMed  CAS  Google Scholar 

  23. Parmar D, Dayal M, Seth, PK: Expression of cytochrome P450s (P450s) in brain: Physiological, pharmacological and toxicological consequences.Proceedings of Indian National Academy of Sciences (PINSA—B) 6: 905–928, 2003

    Google Scholar 

  24. Anandatheerthavarada HK, Shankar SK, Bhamre S, Boyd MR, Song BJ, Ravindranath V: Induction of brain cytochrome P—450 IIE1 by chronic ethanoltreatment. Brain Res. 601: 279–785, 1993

    Article  PubMed  CAS  Google Scholar 

  25. Upadhya SC, Tirumalai PS, Boyd MR, Mori T, Ravindranath V: Cytochrome P4502E1 in brain: constitutive expression, induction by ethanol andlocalization by fluorescence in situ hybridization. Arch Biochem. Biophys 373: 23–34, 2000

    Article  PubMed  CAS  Google Scholar 

  26. Nissbrandt H, Bergquist F, Jonason J, Engberg G: Inhibition of cytochrome P4502E1 induces an increase in extracellular dopamine in ratsubstantia nigra: A new metabolic pathway? Synapse 40: 294–301, 2001

    Article  PubMed  CAS  Google Scholar 

  27. Vaglini F, Pardini C, Viaggi C, Bartoli C, Dinucci D, Corsini GU: Involvement of cytochrome P450 2E1 in the 1-methyl-4-phenyl-1,2,3,6—tetrahydropyridine—induced mouse model ofParkinson's disease. J Neurochem 91: 285–298, 2004

    Article  PubMed  CAS  Google Scholar 

  28. Streetman DS, Bertino JS Jr, Nafziger AN: Phenotyping of drug metabolizing enzymrs in adults: a review of in vivo cytochrome P450phenotyping probes. Pharmacogenetics 10: 187–216, 2000

    Article  PubMed  CAS  Google Scholar 

  29. Glowinski J, Iversen L L: Regional studies of catecholamines in the rat brain. I. The disposition of ‘H-norepinephrine, ‘H-dopamine and ’HDOPAin various regions of the brain. J Neurochem 13: 655–669, 1996

    Article  Google Scholar 

  30. Chomczynski P, Sacchi N: Single step method of RNA isolation by acid guanidium thiocyanate — phenol chloroform extraction. Anal. Bichem 162:156–159, 1987

    Article  CAS  Google Scholar 

  31. Soh Y, Rhee HM, Dong HS, Song BJ: Immunological detection CYP 2E1 in fresh rat lymphocytes and its pretranslational induction by fasting.Biochem and Biophys. Res. Commun. 227: 541–546, 1996

    Article  CAS  Google Scholar 

  32. Castanguay A, Lin D, Stroner GD, Rook P, Furuya K. Hecht SS, Schul HAG, Klaunig JE: Comparative carcinogenenicity in A/J mice and metabolism by cultured mouse peripheral lung of N'—nitrosonornlcodine, 4—(methylnitrosoamino)—1—(3—pyridyll)—1— butanonoe and their analogs. CancerRes. 43: 1223–1229, 1983

    Google Scholar 

  33. Hodgson AV, White TB, White JW, Strobel HW: Expression analysis of the mixed function oxidase system in rat brain by the polymerase chainreaction; Mol. Cell. Biochem. 120: 171–179, 1993

    Article  PubMed  CAS  Google Scholar 

  34. Lucas D, Berthou F, Dreano Y, Lozach P, Volant A, Menez JF: Comparison of levels of cytochrome P450, CYP1A2, CYP2E1, and their related monooxygenase activities in human surgical liver samples. Alcohol Clin ExpRes. 17: 900–905, 1993

    Article  CAS  Google Scholar 

  35. Medvedeva TN: A comparative study of the composition of the microsomal membranes of the liver, brain and skeletal muscles in vertebrates. Zh EvolBiokhim Fiziol 27: 694–700, 1991

    CAS  Google Scholar 

  36. Bourre JM: Roles of unsaturated fatty acids (especially omega—3 fattyacids) in the brain at various ages and during ageing. J Nutr Health Aging 8: 163–174, 2004

    PubMed  CAS  Google Scholar 

  37. Howard LA, Miksys S, Hoffmann E, Mash D, Tyndale RF: Brain CYP2E1 is induced by nicotine and ethanol in rat and is higher in smokers and alcoholics. Br J Pharmacol 138: 1376–1386,2003

    Article  PubMed  CAS  Google Scholar 

  38. Yoo JS, Ishizaki H, Yang CS: Enzyme kinetics of N—nitrosodimethylaminedemethylase in rodents and humans. IARC Sci Publ. 105: 366–369, 1991

    PubMed  CAS  Google Scholar 

  39. Tu YY, Yang CS: High—affinity nitrosamine dealkylase system in rat livermicrosomes and its induction by fasting. Cancer Res. 43: 623–629, 1983

    PubMed  CAS  Google Scholar 

  40. Reed CJ, Lock EA, and De Matteis F: Olfactory cytochrome P450; studieswith suicide substrates of the hemoprotein. J Biochem 253: 569–576, 1998

    Google Scholar 

  41. Irle E, Markowitsch HJ: Widespread neuroanatomical damage and learning deficits following chronic alcohol consumption or vitamin—B1(thiamine) deficiency in rats. Behav. Brain Res. 9: 277–294, 1983

    Article  PubMed  CAS  Google Scholar 

  42. Bellis MDD, Clark DB, Beers SR, Soloff PH, Boring AM, Hall J, Kersh A, Keshavan MS: Hippocampal volume in adolescent—onset alcohol usedisorders. Am. J. Psychiatry 157: 737–744, 2000

    Article  PubMed  Google Scholar 

  43. Laakso MP, Vaurio O, Savolainen L, Repo E, Soininen H, Aronen HJ, Tihonen J: A volume tri MRI study of the hippocampus in type 1 and 2alcoholism. Behav. Brain Res. 109: 177–186, 2000

    Article  PubMed  CAS  Google Scholar 

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Authors and Affiliations

  1. Industrial Toxicology Research Centre, P.O. Box 80, Mahatma Gandhi Marg, Lucknow, 226 001, INDIA

    Sanjay Yadav, Alok Dhawan, Prahlad K. Seth & Devendra Parmar

  2. Department of Biochemistry, Dr. R.M.L. Avadh University, Faizabad, INDIA

    Ram L. Singh

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  1. Sanjay Yadav
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  2. Alok Dhawan
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  3. Ram L. Singh
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  4. Prahlad K. Seth
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  5. Devendra Parmar
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Correspondence to Devendra Parmar.

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Yadav, S., Dhawan, A., Singh, R.L. et al. Expression of constitutive and inducible cytochrome P450 2E1 in rat brain. Mol Cell Biochem 286, 171–180 (2006). https://doi.org/10.1007/s11010-005-9109-z

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