Abstract
The emerging research on biomarkers in alcohol dependence has lead to a deeper understanding of the neurobiological mechanisms in alcoholism. The molecular networks and the pathophysiological circuits are complex and not completely unrevealed up to now. One of the most interesting biomarkers described to play an important role in alcohol dependence is the amino-acid homocysteine, which has particularly been linked with brain atrophy and withdrawal seizures. However, the molecular networks of homocysteine are complex and include an important impact on epigenetic regulation via homocysteine's action as a methyl-group donator in human metabolism. So, alterations in human homocysteine levels can influence DNA-methylation of specific gene areas which may change expression and synthesis of proteins possibly important for the genesis and maintenance of alcohol dependence.
References
-
1
Abdolmaleky HM, Faraone SV, Glatt SJ. et al .
Meta-analysis of association between the T102C polymorphism of the 5HT2a receptor gene and schizophrenia.
Schizophr Res.
2004;
67
53-62
-
2
Abdolmaleky HM, Smith CL, Faraone SV. et al .
Methylomics in psychiatry: Modulation of gene-environment interactions may be through DNA methylation.
Am J Med Genet B Neuropsychiatr Genet.
2004;
127
51-59
-
3
Agartz I, Momenan R, Rawlings RR. et al .
Hippocampal volume in patients with alcohol dependence.
Arch Gen Psychiatry.
1999;
56
356-363
-
4
Althausen S, Paschen W.
Homocysteine-induced changes in mRNA levels of genes coding for cytoplasmic- and endoplasmic reticulum-resident stress proteins in neuronal cell cultures.
Brain Res Mol Brain Res.
2000;
84
32-40
-
5
Austin RC, Sood SK, Dorward AM. et al .
Homocysteine-dependent alterations in mitochondrial gene expression, function and structure. Homocysteine and H2O2 act synergistically to enhance mitochondrial damage.
J Biol Chem.
1998;
273
30808-30817
-
6
Bayerlein K, Hillemacher T, Reulbach U. et al .
Alcoholism-associated hyperhomocysteinemia and previous withdrawal seizures.
Biol Psychiatry.
2005;
57
1590-1593
-
7
Bisaga A, Popik P.
In search of a new pharmacological treatment for drug and alcohol addiction: N-methyl-D-aspartate (NMDA) antagonists.
Drug Alcohol Depend.
2000;
59
1-15
-
8
Bjelland I, Tell GS, Vollset SE. et al .
Folate, vitamin B12, homocysteine, and the MTHFR 677C->T polymorphism in anxiety and depression: the Hordaland Homocysteine Study.
Arch Gen Psychiatry.
2003;
60
618-626
-
9
Bleich S, Bandelow B, Javaheripour K. et al .
Hyperhomocysteinemia as a new risk factor for brain shrinkage in patients with alcoholism.
Neurosci Lett.
2003;
335
179-182
-
10
Bleich S, Bayerlein K, Hillemacher T. et al .
An assessment of the potential value of elevated homocysteine in predicting alcohol-withdrawal seizures.
Epilepsia.
2006;
47
934-938
-
11
Bleich S, Bleich K, Kropp S. et al .
Moderate alcohol consumption in social drinkers raises plasma homocysteine levels: a contradiction to the ‘French Paradox’?.
Alcohol Alcohol.
2001;
36
189-192
-
12
Bleich S, Carl M, Bayerlein K. et al .
Evidence of increased homocysteine levels in alcoholism: the Franconian alcoholism research studies (FARS).
Alcohol Clin Exp Res.
2005;
29
334-336
-
13
Bleich S, Degner D, Bandelow B. et al .
Plasma homocysteine is a predictor of alcohol withdrawal seizures.
Neuroreport.
2000;
11
2749-2752
-
14
Bleich S, Degner D, Javaheripour K. et al .
Homocysteine and alcoholism.
J Neural Transm.
2000;
60 (Suppl)
187-196
-
15
Bleich S, Degner D, Kropp S. et al .
Red wine, spirits, beer and serum homocysteine.
Lancet.
2000;
356
512
-
16
Bleich S, Degner D, Sperling W. et al .
Homocysteine as a neurotoxin in chronic alcoholism.
Prog Neuropsychopharmacol Biol Psychiatry.
2004;
28
453-464
-
17
Bleich S, Degner D, Wiltfang J. et al .
Elevated homocysteine levels in alcohol withdrawal.
Alcohol Alcohol.
2000;
35
351-354
-
18
Bleich S, Frieling H, Hillemacher T.
Elevated Prenatal Homocysteine Levels and the Risk of Schizophrenia.
Arch Gen Psychiatry.
2007;
64
980-981
-
19
Bleich S, Kornhuber J.
Relationship between plasma homocysteine levels and brain atrophy in healthy elderly individuals.
Neurology.
2003;
60
1220
, author reply 1220
-
20
Bleich S, Lenz B, Ziegenbein M. et al .
Epigenetic DNA hypermethylation of the HERP gene promoter induces down-regulation of its mRNA expression in patients with alcohol dependence.
Alcohol Clin Exp Res.
2006;
30
587-591
-
21
Bleich S, Lenz B, Ziegenbein M. et al .
Epigenetic DNA hypermethylation of the HERP gene promoter induces down-regulation of its mRNA expression in patients with alcohol dependence.
Alcohol Clin Exp Res.
2006;
30
587-591
-
22
Bleich S, Spilker K, Kurth C. et al .
Oxidative stress and an altered methionine metabolism in alcoholism.
Neurosci Lett.
2000;
293
171-174
-
23
Bleich S, Wilhelm J, Graesel E. et al .
Apolipoprotein E epsilon 4 is associated with hippocampal volume reduction in females with alcoholism.
J Neural Transm.
2003;
110
401-411
-
24
Bönsch D, Lenz B, Kornhuber J. et al .
DNA hypermethylation of the alpha synuclein promoter in patients with alcoholism.
Neuroreport.
2005;
16
167-170
-
25
Bönsch D, Lenz B, Reulbach U. et al .
Homocysteine associated genomic DNA hypermethylation in patients with chronic alcoholism.
J Neural Transm.
2004;
111
1611-1616
-
26
Bönsch D, Reulbach U, Bayerlein K. et al .
Elevated alpha synuclein mRNA levels are associated with craving in patients with alcoholism.
Biol Psychiatry.
2004;
56
984-986
-
27
Brown AS, Bottiglieri T, Schaefer CA. et al .
Elevated prenatal homocysteine levels as a risk factor for schizophrenia.
Arch Gen Psychiatry.
2007;
64
31-39
-
28
Carboni S, Isola R, Gessa GL. et al .
Ethanol prevents the glutamate release induced by N-methyl-D-aspartate in the rat striatum.
Neurosci Lett.
1993;
152
133-136
-
29
Castro R, Rivera I, Struys EA. et al .
Increased homocysteine and S-adenosylhomocysteine concentrations and DNA hypomethylation in vascular disease.
Clin Chem.
2003;
49
1292-1296
-
30
Chan SL, Fu W, Zhang P. et al .
Herp stabilizes neuronal Ca2+ homeostasis and mitochondrial function during endoplasmic reticulum stress.
J Biol Chem.
2004;
279
28733-28743
-
31
Chen X, Michaelis ML, Michaelis EK.
Effects of chronic ethanol treatment on the expression of calcium transport carriers and NMDA/glutamate receptor proteins in brain synaptic membranes.
J Neurochem.
1997;
69
1559-1569
-
32
Clarke R, Smith AD, Jobst KA. et al .
Folate, vitamin B12, and serum total homocysteine levels in confirmed Alzheimer disease.
Arch Neurol.
1998;
55
1449-1455
-
33
Cravo ML, Gloria LM, Selhub J. et al .
Hyperhomocysteinemia in chronic alcoholism: correlation with folate, vitamin B-12, and vitamin B-6 status.
Am J Clin Nutr.
1996;
63
220-224
-
34
D’Emilia DM, Lipton SA.
Ratio of S-nitrosohomocyst(e)ine to homocyst(e)ine or other thiols determines neurotoxicity in rat cerebrocortical cultures.
Neurosci Lett.
1999;
265
103-106
-
35
Danysz W, Dyr W, Jankowska E. et al .
The involvement of NMDA receptors in acute and chronic effects of ethanol.
Alcohol Clin Exp Res.
1992;
16
499-504
-
36
Davidson M, Shanley B, Wilce P.
Increased NMDA-induced excitability during ethanol withdrawal: a behavioural and histological study.
Brain Res.
1995;
674
91-96
-
37
Detich N, Hamm S, Just G. et al .
The methyl donor S-Adenosylmethionine inhibits active demethylation of DNA: a candidate novel mechanism for the pharmacological effects of S-Adenosylmethionine.
J Biol Chem.
2003;
278
20812-20820
-
38
Doerfler W.
DNA methylation and gene activity.
Annu Rev Biochem.
1983;
52
93-124
-
39
Egger G, Liang G, Aparicio A. et al .
Epigenetics in human disease and prospects for epigenetic therapy.
Nature.
2004;
429
457-463
-
40
Folbergrova J.
Anticonvulsant action of both NMDA and non-NMDA receptor antagonists against seizures induced by homocysteine in immature rats.
Exp Neurol.
1997;
145
442-450
-
41
Folbergrova J, Haugvicova R, Mares P.
Behavioral and metabolic changes in immature rats during seizures induced by homocysteic acid: the protective effect of NMDA and non-NMDA receptor antagonists.
Exp Neurol.
2000;
161
336-345
-
42
Follesa P, Ticku MK.
Chronic ethanol-mediated up-regulation of the N-methyl-D-aspartate receptor polypeptide subunits in mouse cortical neurons in culture.
J Biol Chem.
1996;
271
13297-13299
-
43
Follesa P, Ticku MK.
NMDA receptor upregulation: molecular studies in cultured mouse cortical neurons after chronic antagonist exposure.
J Neurosci.
1996;
16
2172-2178
-
44
Folstein M, Liu T, Peter I. et al .
The homocysteine hypothesis of depression.
Am J Psychiatry.
2007;
164
861-867
-
45
Frieling H, Bleich S, Otten J. et al .
Epigenetic Downregulation of Atrial Natriuretic Peptide but not Vasopressin mRNA Expression in Females with Eating Disorders is Related to Impulsivity.
Neuropsychopharmacology.
2008;
33
2605-2609
-
46
Frieling H, Gozner A, Römer KD. et al .
Global DNA hypomethylation and DNA hypermethylation of the alpha synuclein promoter in females with anorexia nervosa.
Mol Psychiatry.
2007;
12
229-230
-
47
Frosst P, Blom HJ, Milos R. et al .
A candidate genetic risk factor for vascular disease: a common mutation in methylenetetrahydrofolate reductase.
Nat Genet.
1995;
10
111-113
-
48
Fuks F, Hurd PJ, Wolf D. et al .
The methyl-CpG-binding protein MeCP2 links DNA methylation to histone methylation.
J Biol Chem.
2003;
278
4035-4040
-
49
Grant KA, Valverius P, Hudspith M. et al .
Ethanol withdrawal seizures and the NMDA receptor complex.
Eur J Pharmacol.
1990;
176
289-296
-
50
Harper C.
The neuropathology of alcohol-specific brain damage, or does alcohol damage the brain?.
J Neuropathol Exp Neurol.
1998;
57
101-110
-
51
Hillemacher T, Bayerlein K, Frieling H. et al .
Elevated prolactin serum levels and history of alcohol withdrawal seizures.
J Psychiatr Res.
2007;
41
702-706
-
52
Hillemacher T, Frieling H, Bayerlein K. et al .
Biological markers to predict previous alcohol withdrawal seizures: a risk assessment.
J Neural Transm.
2007;
114
151-154
-
53
Hillemacher T, Frieling H, Hartl T. et al .
Promoter specific methylation of the dopamine transporter gene is altered in alcohol dependence and associated with craving.
J Psychiatr Res.
2009;
43
388-392
-
54
Hillemacher T, Frieling H, Luber K. et al .
Epigenetic regulation and gene expression of vasopressin and atrial natriuretic peptide in alcohol withdrawal.
Psychoneuroendocrinology.
2008;
, DOI:10.1016/j.psyneuen.2008.1010.1019
-
55
Hillemacher T, Frieling H, Moskau S. et al .
Global DNA methylation is influenced by smoking behaviour.
Eur Neuropsychopharmacol.
2008;
18
295-298
-
56
Hillemacher T, Reulbach U, Bayerlein K. et al .
Plasma homocysteine concentrations do not influence craving in alcohol withdrawal.
Alcohol.
2004;
34
211-215
-
57
Hoffman PL, Rabe CS, Grant KA. et al .
Ethanol and the NMDA receptor.
Alcohol.
1990;
7
229-231
-
58
Holliday R.
DNA methylation and epigenetic defects in carcinogenesis.
Mutat Res.
1987;
181
215-217
-
59
Hu XJ, Follesa P, Ticku MK.
Chronic ethanol treatment produces a selective upregulation of the NMDA receptor subunit gene expression in mammalian cultured cortical neurons.
Brain Res Mol Brain Res.
1996;
36
211-218
-
60
Huang RF, Huang SM, Lin BS. et al .
Homocysteine thiolactone induces apoptotic DNA damage mediated by increased intracellular hydrogen peroxide and caspase 3 activation in HL-60 cells.
Life Sci.
2001;
68
2799-2811
-
61
Hultberg B, Berglund M, Andersson A. et al .
Elevated plasma homocysteine in alcoholics.
Alcohol Clin Exp Res.
1993;
17
687-689
-
62
Ingrosso D, Cimmino A, Perna AF. et al .
Folate treatment and unbalanced methylation and changes of allelic expression induced by hyperhomocysteinaemia in patients with uraemia.
Lancet.
2003;
361
1693-1699
-
63
Kenyon SH, Nicolaou A, Gibbons WA.
The effect of ethanol and its metabolites upon methionine synthase activity in vitro.
Alcohol.
1998;
15
305-309
-
64
Kim WK, Pae YS.
Involvement of N-methyl-d-aspartate receptor and free radical in homocysteine-mediated toxicity on rat cerebellar granule cells in culture.
Neurosci Lett.
1996;
216
117-120
-
65
Kokame K, Agarwala KL, Kato H. et al .
Herp, a new ubiquitin-like membrane protein induced by endoplasmic reticulum stress.
J Biol Chem.
2000;
275
32846-32853
-
66
Koob GF, Mason BJ, De Witte P. et al .
Potential neuroprotective effects of acamprosate.
Alcohol Clin Exp Res.
2002;
26
586-592
-
67
Kornhuber J, Kaiserauer CH, Kornhuber AW. et al .
Alcohol consumption and blood-cerebrospinal fluid barrier dysfunction in man.
Neurosci Lett.
1987;
79
218-222
-
68
Kornhuber J, Weller M.
Psychotogenicity and N-methyl-D-aspartate receptor antagonism: implications for neuroprotective pharmacotherapy.
Biol Psychiatry.
1997;
41
135-144
-
69
Kril JJ, Halliday GM.
Brain shrinkage in alcoholics: a decade on and what have we learned?.
Prog Neurobiol.
1999;
58
381-387
-
70
Kruman II, Culmsee C, Chan SL. et al .
Homocysteine elicits a DNA damage response in neurons that promotes apoptosis and hypersensitivity to excitotoxicity.
J Neurosci.
2000;
20
6920-6926
-
71
Kruman II, Kumaravel TS, Lohani A. et al .
Folic acid deficiency and homocysteine impair DNA repair in hippocampal neurons and sensitize them to amyloid toxicity in experimental models of Alzheimer's disease.
J Neurosci.
2002;
22
1752-1762
-
72
Kubova H, Folbergrova J, Mares P.
Seizures induced by homocysteine in rats during ontogenesis.
Epilepsia.
1995;
36
750-756
-
73
Kurth C, Wegerer V, Degner D. et al .
Risk assessment of alcohol withdrawal seizures with a Kohonen feature map.
Neuroreport.
2001;
12
1235-1238
-
74
Lenz B, Bleich S, Beutler S. et al .
Homocysteine regulates expression of Herp by DNA methylation involving the AARE and CREB binding sites.
Exp Cell Res.
2006;
312
4049-4055
-
75
Liang T, Spence J, Liu L. et al .
alpha-Synuclein maps to a quantitative trait locus for alcohol preference and is differentially expressed in alcohol-preferring and -nonpreferring rats.
Proc Natl Acad Sci USA.
2003;
100
4690-4695
-
76
Liljequist S.
The competitive NMDA receptor antagonist, CGP 39551, inhibits ethanol withdrawal seizures.
Eur J Pharmacol.
1991;
192
197-198
-
77
Lipton SA, Kim WK, Choi YB. et al .
Neurotoxicity associated with dual actions of homocysteine at the N-methyl-D-aspartate receptor.
Proc Natl Acad Sci USA.
1997;
94
5923-5928
-
78
Lopez-Serra L, Ballestar E, Fraga MF. et al .
A profile of methyl-CpG binding domain protein occupancy of hypermethylated promoter CpG islands of tumor suppressor genes in human cancer.
Cancer Res.
2006;
66
8342-8346
-
79
Lovinger DM.
Alcohols and neurotransmitter gated ion channels: past, present and future.
Naunyn Schmiedebergs Arch Pharmacol.
1997;
356
267-282
-
80
Lovinger DM.
Excitotoxicity and alcohol-related brain damage.
Alcohol Clin Exp Res.
1993;
17
19-27
-
81
Maler JM, Seifert W, Huther G. et al .
Homocysteine induces cell death of rat astrocytes in vitro.
Neurosci Lett.
2003;
347
85-88
-
82
Mash DC, Ouyang Q, Pablo J. et al .
Cocaine abusers have an overexpression of alpha-synuclein in dopamine neurons.
J Neurosci.
2003;
23
2564-2571
-
83
Mattson MP, Shea TB.
Folate and homocysteine metabolism in neural plasticity and neurodegenerative disorders.
Trends Neurosci.
2003;
26
137-146
-
84
Mayer ML, Westbrook GL.
The physiology of excitatory amino acids in the vertebrate central nervous system.
Prog Neurobiol.
1987;
28
197-276
-
85
MacKeever MP, Weir DG, Molloy A. et al .
Betaine-homocysteine methyltransferase: organ distribution in man, pig and rat and subcellular distribution in the rat.
Clin Sci (Lond).
1991;
81
551-556
-
86
Moghaddam B, Bolinao ML.
Biphasic effect of ethanol on extracellular accumulation of glutamate in the hippocampus and the nucleus accumbens.
Neurosci Lett.
1994;
178
99-102
-
87
Morrisett RA, Rezvani AH, Overstreet D. et al .
MK-801 potently inhibits alcohol withdrawal seizures in rats.
Eur J Pharmacol.
1990;
176
103-105
-
88
Nan X, Ng HH, Johnson CA. et al .
Transcriptional repression by the methyl-CpG-binding protein MeCP2 involves a histone deacetylase complex.
Nature.
1998;
393
386-389
-
89
Nonaka H, Tsujino T, Watari Y. et al .
Taurine prevents the decrease in expression and secretion of extracellular superoxide dismutase induced by homocysteine: amelioration of homocysteine-induced endoplasmic reticulum stress by taurine.
Circulation.
2001;
104
1165-1170
-
90
O’Neill J, Cardenas VA, Meyerhoff DJ.
Effects of abstinence on the brain: quantitative magnetic resonance imaging and magnetic resonance spectroscopic imaging in chronic alcohol abuse.
Alcohol Clin Exp Res.
2001;
25
1673-1682
-
91
Outinen PA, Sood SK, Liaw PC. et al .
Characterization of the stress-inducing effects of homocysteine.
Biochem J.
1998;
332
((Pt 1))
213-221
-
92
Perez RG, Waymire JC, Lin E. et al .
A role for alpha-synuclein in the regulation of dopamine biosynthesis.
J Neurosci.
2002;
22
3090-3099
-
93
Pfefferbaum A, Sullivan EV, Mathalon DH. et al .
Longitudinal changes in magnetic resonance imaging brain volumes in abstinent and relapsed alcoholics.
Alcohol Clin Exp Res.
1995;
19
1177-1191
-
94
Phillips PE, Stuber GD, Heien ML. et al .
Subsecond dopamine release promotes cocaine seeking.
Nature.
2003;
422
614-618
-
95
Prins ND, Den Heijer T, Hofman A. et al .
Homocysteine and cognitive function in the elderly: the Rotterdam Scan Study.
Neurology.
2002;
59
1375-1380
-
96
Rady PL, Szucs S, Grady J. et al .
Genetic polymorphisms of methylenetetrahydrofolate reductase (MTHFR) and methionine synthase reductase (MTRR) in ethnic populations in Texas; a report of a novel MTHFR polymorphic site, G1793A.
Am J Med Genet.
2002;
107
162-168
-
97
Rodenhiser D, Mann M.
Epigenetics and human disease: translating basic biology into clinical applications.
Cmaj.
2006;
174
341-348
-
98
Rozen R.
Genetic modulation of homocysteinemia.
Semin Thromb Hemost.
2000;
26
255-261
-
99
Sachdev PS, Valenzuela M, Wang XL. et al .
Relationship between plasma homocysteine levels and brain atrophy in healthy elderly individuals.
Neurology.
2002;
58
1539-1541
-
100
Selhub J.
Homocysteine metabolism.
Annu Rev Nutr.
1999;
19
217-246
-
101
Smith SS, Crocitto L.
DNA methylation in eukaryotic chromosome stability revisited: DNA methyltransferase in the management of DNA conformation space.
Mol Carcinog.
1999;
26
1-9
-
102
Snell LD, Nunley KR, Lickteig RL. et al .
Regional and subunit specific changes in NMDA receptor mRNA and immunoreactivity in mouse brain following chronic ethanol ingestion.
Brain Res Mol Brain Res.
1996;
40
71-78
-
103
Stickel F, Choi SW, Kim YI. et al .
Effect of chronic alcohol consumption on total plasma homocysteine level in rats.
Alcohol Clin Exp Res.
2000;
24
259-264
-
104
Sunden SL, Renduchintala MS, Park EI. et al .
Betaine-homocysteine methyltransferase expression in porcine and human tissues and chromosomal localization of the human gene.
Arch Biochem Biophys.
1997;
345
171-174
-
105
Tsai G, Coyle JT.
The role of glutamatergic neurotransmission in the pathophysiology of alcoholism.
Annu Rev Med.
1998;
49
173-184
-
106
Tsai GE, Ragan P, Chang R. et al .
Increased glutamatergic neurotransmission and oxidative stress after alcohol withdrawal.
Am J Psychiatry.
1998;
155
726-732
-
107
Ubbink JB, Becker PJ, Vermaak WJ. et al .
Results of B-vitamin supplementation study used in a prediction model to define a reference range for plasma homocysteine.
Clin Chem.
1995;
41
1033-1037
-
108
Veldic M, Caruncho HJ, Liu WS. et al .
DNA-methyltransferase 1 mRNA is selectively overexpressed in telencephalic GABAergic interneurons of schizophrenia brains.
Proc Natl Acad Sci USA.
2004;
101
348-353
-
109
Wilhelm J, Bayerlein K, Hillemacher T. et al .
Short-term cognition deficits during early alcohol withdrawal are associated with elevated plasma homocysteine levels in patients with alcoholism.
J Neural Transm.
2006;
113
357-363
-
110
Yi P, Melnyk S, Pogribna M. et al .
Increase in plasma homocysteine associated with parallel increases in plasma S-adenosylhomocysteine and lymphocyte DNA hypomethylation.
J Biol Chem.
2000;
275
29318-29323
Correspondence
S. BleichMD
Department of Psychiatry
Socialpsychiatry and Psychotherapy
Medical School Hannover
Carl-Neuberg-Str. 1
30625 Hannover
Germany
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Fax: +49/511/532 24 15
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