Abstract
Ethanol consumption has effects on the central nervous system (CNS), manifesting as motor incoordination, sleep induction (hypnosis), anxiety, amnesia, and the reinforcement or aversion of alcohol consumption. Acetaldehyde (the direct metabolite of ethanol oxidation) contributes to many aspects of the behavioral effects of ethanol. Given acetaldehyde cannot pass through the blood brain barrier, its concentration in the CNS is primarily determined by local production from ethanol. Catalase and cytochrome P450 2E1 (CYP2E1) represent the major enzymes in the CNS that catalyze ethanol oxidation. CYP2E1 is expressed abundantly within the microsomes of certain brain cells and is localized to particular brain regions. This chapter focuses on the discussion of CYP2E1 in ethanol metabolism in the CNS, covering topics including how it is regulated, where it is expressed and how it influences sensitivity to ethanol in the brain.
Access this chapter
Tax calculation will be finalised at checkout
Purchases are for personal use only
Similar content being viewed by others
References
Abdulla D, Goralski KB et al (2006) The regulation of cytochrome P450 2E1 during LPS-induced inflammation in the rat. Toxicol Appl Pharmacol 216(1):1–10
Alfonso-Loeches S, Guerri C (2011) Molecular and behavioral aspects of the actions of alcohol on the adult and developing brain. Crit Rev Clin Lab Sci 48(1):19–47
Aragon CM, Rogan F et al (1992) Ethanol metabolism in rat brain homogenates by a catalase-H2O2 system. Biochem Pharmacol 44(1):93–98
Bansal S, Liu CP et al (2010) Mitochondria-targeted cytochrome P450 2E1 induces oxidative damage and augments alcohol-mediated oxidative stress. J Biol Chem 285(32):24609–24619
Beisswenger TB, Holmquist B et al (1985) chi-ADH is the sole alcohol dehydrogenase isozyme of mammalian brains: implications and inferences. Proc Natl Acad Sci USA 82(24):8369–8373
Bhave SV, Hoffman PL et al (2006) Gene array profiles of alcohol and aldehyde metabolizing enzymes in brains of C57BL/6 and DBA/2 mice. Alcohol Clin Exp Res 30(10):1659–1669
Brust JC (2010) Ethanol and cognition: indirect effects, neurotoxicity and neuroprotection: a review. Int J Environ Res Public Health 7(4):1540–1557
Cheung C, Yu AM et al (2005) The cyp2e1-humanized transgenic mouse: role of cyp2e1 in acetaminophen hepatotoxicity. Drug Metab Dispos 33(3):449–457
Correa M, Arizzi MN et al (2003) Open field locomotor effects in rats after intraventricular injections of ethanol and the ethanol metabolites acetaldehyde and acetate. Brain Res Bull 62(3):197–202
Correa M, Manrique HM et al (2008) Reduction in the anxiolytic effects of ethanol by centrally formed acetaldehyde: the role of catalase inhibitors and acetaldehyde-sequestering agents. Psychopharmacology (Berl) 200(4):455–464
Davis VE, Walsh MJ (1970) Alcohol, amines, and alkaloids: a possible biochemical basis for alcohol addiction. Science 167(3920):1005–1007
Deitrich RA (2004) Acetaldehyde: Deja vu du jour. J Stud Alcohol 65(5):557–572
Deitrich R (2011) Ethanol as a prodrug: brain metabolism of ethanol mediates its reinforcing effects–a commentary. Alcohol Clin Exp Res 35(4):581–583
Deitrich RA, Dunwiddie TV et al (1989) Mechanism of action of ethanol – initial central-nervous-system actions. Pharmacol Rev 41(4):489–537
Deitrich R, Zimatkin S et al (2006) Oxidation of ethanol in the brain and its consequences. Alcohol Res Health 29(4):266–273
Dey A, Kumar SM (2011) Cytochrome P450 2E1 and hyperglycemia-induced liver injury. Cell Biol Toxicol 27(4):285–310
Edenberg HJ (1998) Genetics of alcoholism. Science 282(5392):1269
Estonius M, Svensson S et al (1996) Alcohol dehydrogenase in human tissues: localisation of transcripts coding for five classes of the enzyme. FEBS Lett 397(2–3):338–342
Galter D, Carmine A et al (2003) Distribution of class I, III and IV alcohol dehydrogenase mRNAs in the adult rat, mouse and human brain. Eur J Biochem 270(6):1316–1326
Gill K, Menez JF et al (1992) Enzymatic production of acetaldehyde from ethanol in rat brain tissue. Alcohol Clin Exp Res 16(5):910–915
Ginter E, Simko V (2009) Alcoholism: recent advances in epidemiology, biochemistry and genetics. Bratisl Lek Listy 110(5):307–311
Hauser SR, Getachew B et al (2012) Nicotine modulates alcohol-seeking and relapse by alcohol-preferring (P) rats in a time-dependent manner. Alcohol Clin Exp Res 36(1):43–54
Howard LA, Ahluwalia JS et al (2003a) CYP2E1*1D regulatory polymorphism: association with alcohol and nicotine dependence. Pharmacogenetics 13(6):321–328
Howard LA, Miksys S et al (2003b) Brain CYP2E1 is induced by nicotine and ethanol in rat and is higher in smokers and alcoholics. Br J Pharmacol 138(7):1376–1386
Karahanian E, Quintanilla ME et al (2011) Ethanol as a prodrug: brain metabolism of ethanol mediates its reinforcing effects. Alcohol Clin Exp Res 35(4):606–612
Kerr JT, Maxwell DS et al (1989) Immunocytochemistry of alcohol dehydrogenase in the rat central nervous system. Alcohol Clin Exp Res 13(6):730–736
Knockaert L, Fromenty B et al (2011) Mechanisms of mitochondrial targeting of cytochrome P450 2E1: physiopathological role in liver injury and obesity. FEBS J 278(22):4252–4260
Lee SS, Buters JT et al (1996) Role of CYP2E1 in the hepatotoxicity of acetaminophen. J Biol Chem 271(20):12063–12067
Lieber CS (1999) Microsomal ethanol-oxidizing system (MEOS): the first 30 years (1968–1998)–a review. Alcohol Clin Exp Res 23(6):991–1007
Martinez SE, Vaglenova J et al (2001) Distribution of alcohol dehydrogenase mRNA in the rat central nervous system. Consequences for brain ethanol and retinoid metabolism. Eur J Biochem 268(19):5045–5056
McBride WJ, Li TK et al (2002) Involvement of acetaldehyde in alcohol addiction. Alcohol Clin Exp Res 26(1):114–119
Melchior CL, Myers RD (1977) Preference for alcohol evoked by tetrahydropapaveroline (THP) chronically infused in the cerebral ventricle of the rat. Pharmacol Biochem Behav 7(1):19–35
Mokdad AH, Marks JS et al (2004) Actual causes of death in the United States, 2000. JAMA 291(10):1238–1245
Person RE, Chen H et al (2000) Enzymic catalysis of the accumulation of acetaldehyde from ethanol in human prenatal cephalic tissues: Evaluation of the relative contributions of CYP2E1, alcohol dehydrogenase, and catalase/peroxidases. Alcohol Clin Exp Res 24(9):1433–1442
Quertemont E, Tambour S et al (2004) Behavioral characterization of acetaldehyde in C57BL/6J mice: locomotor, hypnotic, anxiolytic and amnesic effects. Psychopharmacology (Berl) 177(1–2):84–92
Quintanilla ME, Tampier L et al (2007) Sex differences, alcohol dehydrogenase, acetaldehyde burst, and aversion to ethanol in the rat: a systems perspective. Am J Physiol Endocrinol Metab 293(2):E531–E537
Raza H, Prabu SK et al (2004) Elevated mitochondrial cytochrome P450 2E1 and glutathione S-transferase A4-4 in streptozotocin-induced diabetic rats: tissue-specific variations and roles in oxidative stress. Diabetes 53(1):185–194
Robin MA, Anandatheerthavarada HK et al (2001) Mitochondrial targeted cytochrome P450 2E1 (P450 MT5) contains an intact N terminus and requires mitochondrial specific electron transfer proteins for activity. J Biol Chem 276(27):24680–24689
Robin MA, Anandatheerthavarada HK et al (2002) Bimodal targeting of microsomal CYP2E1 to mitochondria through activation of an N-terminal chimeric signal by cAMP-mediated phosphorylation. J Biol Chem 277(43):40583–40593
Rodd-Henricks ZA, Melendez RI et al (2002) The reinforcing effects of acetaldehyde in the posterior ventral tegmental area of alcohol-preferring rats. Pharmacol Biochem Behav 72(1–2):55–64
Sarc L, Wraber B et al (2011) Ethanol and acetaldehyde disturb TNF-alpha and IL-6 production in cultured astrocytes. Hum Exp Toxicol 30(9):1256–1265
Tabakoff B, Anderson RA et al (1976) Brain acetaldehyde after ethanol administration. Biochem Pharmacol 25(11):1305–1309
Thurman RG, Ley HG et al (1972) Hepatic microsomal ethanol oxidation. Hydrogen peroxide formation and the role of catalase. Eur J Biochem 25(3):420–430
Tindberg N, Baldwin HA et al (1996) Induction of cytochrome P450 2E1 expression in rat and gerbil astrocytes by inflammatory factors and ischemic injury. Mol Pharmacol 50(5):1065–1072
Vangipuram SD, Lyman WD (2010) Ethanol alters cell fate of fetal human brain-derived stem and progenitor cells. Alcohol Clin Exp Res 34(9):1574–1583
Vasiliou V, Ziegler TL et al (2006) CYP2E1 and catalase influence ethanol sensitivity in the central nervous system. Pharmacogenet Genomics 16(1):51–58
Vemuri MC, Chetty CS (2005) Alcohol impairs astrogliogenesis by stem cells in rodent neurospheres. Neurochem Int 47(1–2):129–135
Westcott JY, Weiner H et al (1980) In vivo acetaldehyde in the brain of the rat treated with ethanol. Biochem Pharmacol 29(3):411–417
Zakhari S (2006) Overview: how is alcohol metabolized by the body? Alcohol Res Health 29(4):245–254
Zimatkin SM (1991) Histochemical study of aldehyde dehydrogenase in the rat CNS. J Neurochem 56(1):1–11
Zimatkin SM, Pronko SP et al (2006) Enzymatic mechanisms of ethanol oxidation in the brain. Alcohol Clin Exp Res 30(9):1500–1505
Zimatkin SM, Oganesian NA et al (2011) Acetate-dependent mechanisms of inborn tolerance to ethanol. Alcohol Alcohol 46(3):233–238
Author information
Authors and Affiliations
Corresponding author
Editor information
Editors and Affiliations
Rights and permissions
Copyright information
© 2013 Springer Science+Business Media Dordrecht
About this chapter
Cite this chapter
Heit, C., Dong, H., Chen, Y., Thompson, D.C., Deitrich, R.A., Vasiliou, V.K. (2013). The Role of CYP2E1 in Alcohol Metabolism and Sensitivity in the Central Nervous System. In: Dey, A. (eds) Cytochrome P450 2E1: Its Role in Disease and Drug Metabolism. Subcellular Biochemistry, vol 67. Springer, Dordrecht. https://doi.org/10.1007/978-94-007-5881-0_8
Download citation
DOI: https://doi.org/10.1007/978-94-007-5881-0_8
Published:
Publisher Name: Springer, Dordrecht
Print ISBN: 978-94-007-5880-3
Online ISBN: 978-94-007-5881-0
eBook Packages: Biomedical and Life SciencesBiomedical and Life Sciences (R0)


