Biología, patobiología y bioclínica de la homocisteína eh la especie humana

Biology, pathobiology and subclinical homocysteine in the human species

La homocistinuria fue descrita en 19a2 en niños con dificultades de aprendizaje y en 19a9 McCully informó la evidencia en autopsias de trombosis arterial eztensa y aterosclerosis en niños con elevadas concentraciones de homocisteína plasmática y homocistinuria. La homocisteína, un aminoácido de azufre, es un metabolito intermedio de la metionina, y sobre la base de estos hallazgos bioquímicos, ellos propusieron que la homocisteína plasmática elevada puede causar lesión neural y enfermedad vascular aterosclerótica. Hoy se considera un factor de riesgo independiente para esta última. La hiperhomocistinemia leve es bastante prevalente en la población general. Puede deberse a defectos genéticos en las enzimas que participan en el metabolismo de la homocisteína, carencias nutricionales de vitaminas y cofactores, ciertos medicamentos, ingesta rica en metionina o enfermedad renal. La alta concentración puede reducirse con folato, y es así que la suplementación vitamínica ha sido propuesta en individuos con hiperhomocistinemia con el fin de reducir su riesgo de enfermedad cardiovascular. En este artículo hacemos una revisión de la biología, la patobiología y la bioclínica del metabolismo de la homocisteína.

1. Ramakrishnan S, Sulochana HN, Lakshmi S et al. Biochemistry of homocysteine in health and diseases. Indian J Biochem Biophys. 2006;43:275-83.
2. Huang T, Yuan G, Xhang X et al. Cardiovascular pathogenesis in hyperhomocysteinemia. Asia Pac J Clin Nutr. 2008;17:8-16.
3. Trabetti E. Homocysteine, MTHFR gene polymorphisms, and cardio-cere- brovascular risk. J Appl Genet. 2008;49:267-82.
4. Obeid R, McCaddon A, Herrmann W. The role of hyperhomocysteinemia and B-vitamin deficiency in neurological and psychiatric diseases. Clin Chem Lab Med. 2007;45:1590-606.
5. Deth R, Muratore C, Benzecry J et al. How environmental and genetic factors combine to cause autism: A redox/methylation hypothesis. Neurotoxicology. 2008;29:190-201.
6. Frankenburg FR. The role of one-carbon metabolism in schizophrenia and depression. Harv Rev Psychiatry. 2007;15:146-60.
7. Folstein M, Liu T, Peter I, Buell J et al. The homocysteine hypothesis of depression. Am J Psychiatry. 2007;164:861-7.
8. Almeida OP, McCaul H, Hankey GJ et al. Homocysteine and depression in later life. Arch Gen Psychiatry. 2008;65:1286-94.
9. Dodds L, Fell DB, Dooley HC et al. Effect of homocysteine concentration in early pregnancy on gestational hypertensive disorders and other pregnancy outcomes. Clin Chem. 2008;54:326-34.
10. Forges T, Pellanda H, Diligent C et al. Do folates have an impact on fertility? Gynecol Obstet Fertil. 2008;36:930-9.
11. Devlin TM. Textbook of Biochemistry with Clinical Correlations, 6a. ed., New York. Wiley-Liss. 2006.
12. Nelson DL, Cox MM. Lehninger Principles of Biochemistry, 5a. ed., New York. W. H. Freeman. 2008.
13. Berg JM, Tymoczko JL, Stryer L. Biochemistry, 6a. ed., New York. W. H. Freeman. 2006.
14. Scriver CR, Sly WS, Childs B, et al. The metabolic and molecular basis of inherited disease, 8a. ed., New York. McGraw-Hill Professional. 2001.
15. OMIM [base de datos en Internet]. Baltimore: Johns Hopkins University; 1966- [fecha de acceso 15 de agosto del 2009]. Disponible en: http:// www.ncbi.nlm.nih.gov/entrez/dispomim
16. HUGO [base de datos en Internet]. Bethesda: National Library of Medicine and others(exp.: Celera Genomics and the Sanger Center); 1989- [fecha de acceso 15 de agosto del 2009]. Disponible en: http://www.hugo- international.org/index.html
17. IUMBM[base de datos en Internet]. London: International Union of Biochemistry and Molecular Biology;1977- [fecha de acceso 15 de agosto del 2009]. Disponible en: http://www.chem.qmul.ac.uk/iupac/jcbn/index.html#2
18. PubMed [base de datos en Internet]. Bethesda: National Library of Medicine; 1966- [fecha de acceso 15 de agosto del 2009]. Disponible en: http:// www.ncbi.nlm.nih.gov/PubMed/
19. EMBASE [base de datos en Internet]. Holanda: Excerpta Medica-Elsevier; 1974-[fecha de acceso 15 de agosto del 2009]. Disponible en: http:// www.embase.com
20. Steensholt G. On the methylation of ethanol amine, dimethyl ethanol amine, guanidine acetic acid and homocysteine. Acta Physiol Scand. 1947;14:340-7.
21. Greenberg DM. Biological methylation. Adv Enzymol Relat Areas Mol Biol. 1963;25:395-431.
22. Pasieka AE, Morgan JF. The detection of homocysteine in biological systems. Biochim Biophys Acta. 1955;18:236-40.
23. Bartosinski B. Biosynthesis of methyl group of methionine. Postepy Biochem. 1964;10:463-74.
24. Langemann H, Hensler CJ. Spontaneous increase in the rate of formation of methionine from dimethylthetin and homocysteine in rat liver homogenates. Arch Biochem. 1951;33:344-5.
25. Gibson F, Woods DD. The synthesis of methionine from homocysteine by
Fscherichia coli. Biochem J. 1952;51(1):v.
26. Eger W. Cysteine, homocysteine, cystathionine & cysteinamine as necrotropic liver protective substances, combined with glucose & fructose. Medizinische. 1957;17:618-23.
27. Trutschel W. Homocysteine-thiolactone, cysteine and fructose therapy of acute and chronic hepatitis. Arztl Wochensch. 1957;12:541-5.
28. Frimpter GW. The disulfide of L-cysteine and L-homocysteine in urine of patients with cystinuria. J Biol Chem. 1961;236:PC51-3.
29. Freycon F, Freycon MT. Homocystinuria. Pediatrie. 1965;20:495-7.
30. Chatagner F. Biochemical aspects of some congenital anomalies of the metabolism of sulfur amino acids. Expos Annu Biochim Med. 1967;28:53-76.
31. Crawhall JC, Watts RW. Cystinuria. Am J Med. 1968;45:736-55.
32. No autores listados. Defective vitamin B 12 metabolism in the human being: changes in methionine and methylmalonic acid excretion. Nutr Rev. 1969;27:202-4.
33. Hogenkamp HP. Enzymatic reactions involving corrinoids. Annu Rev Biochem. 1968;37:225-45.
34. Bertino JR, Hillcoat BL. Regulation of dihydrofolate reductase and other folate-requiring enzymes. Adv Enzyme Regul. 1968;6:335-49.
35. Sakami W, Stevens A. Synthesis and properties of adenosyl-L-homocysteine. Bull Soc Chim Biol (Paris). 1958;40:1787-93.
36. Lombardini JB, Talalay P. Formation, functions and regulatory importance of S-adenosyl-L-methionine. Adv Enzyme Regul. 1970;9:349-84.
37. Weissbach H, Taylor RT. Roles of vitamin B 12 and folic acid in methionine synthesis. Vitam Horm. 1970;28:415-40.
38. Mahoney MJ, Rosenberg LE. Inherited defects of B12 metabolism. Am J Med. 1970;48:584-93.
39. Waxman S, Corcino JJ, Herbert V. Drugs, toxins and dietary amino acids affecting vitamin B12 or folic acid absorption or utilization. Am J Med. 1970;48:599-608.
40. Hoffbrand AV, Waters AH. Observations on the biochemical basis of megaloblastic anaemia. Br J Haematol. 1972;23:Suppl:109-18.
41. Brosnan JT, Brosnan ME. The sulfur-containing amino acids: an overview. J Nutr. 2006;136(6 Suppl):1636S-1640S.
42. Pajares MA, Pérez-Sala D. Betaine homocysteine S-methyltransferase: just a regulator of homocysteine metabolism? Cell Mol Life Sci. 2006;63:2792-803.
43. Yamanishi M, Habil O, Sen S et al. Structural insights into pathogenic mutations in heme-dependent cystathionine-beta-synthase. J Inorg Biochem. 2006;100:1988-95.
44. Brosnan JT, da Silva R, Brosnan ME. Amino acids and the regulation of methyl balance in humans. Curr Opin Clin Nutr Metab Care. 2007;10:52-7.
45. Burrin DG, Stoll B. Emerging aspects of gut sulfur amino acid metabolism. Curr Opin Clin Nutr Metab Care. 2007;10:63-8.
46. Markham GD, Pajares MA. Structure-function relationships in methionine adenosyltransferases. Cell Mol Life Sci. 2009;66:636-48.
47. Loenen WA. S-adenosylmethionine: jack of all trades and master of everything? Biochem Soc Trans. 2006;34(Pt 2):330-3.
48. Roje S. S-Adenosyl-L-methionine: beyond the universal methyl group donor. Phytochemistry. 2006;67:1686-98.
49. Finkelstein JD. Metabolic regulatory properties of S-adenosylmethionine and S-adenosylhomocysteine. Clin Chem Lab Med. 2007;45:1694-9.
50. Grillo MA, Colombatto S. S-adenosylmethionine and its products. Amino Acids. 2008;34:187-93.
51. Matthews RG, Elmore CL. Defects in homocysteine metabolism: diversity among hyperhomocyst(e)inemias. Clin Chem Lab Med. 2007;45:1700-3.
52. Xhou J,Austin RC. Contributions of hyperhomocysteinemia to atherosclerosis: Causal relationship and potential mechanisms. Biofactors. 2009;35:120-9.
53. Hoþoleanu C, Porojan-Iuga M, Rusu ML et al. Hyperhomocysteinemia: clinical and therapeutical involvement in venous thrombosis. Rom J Intern Med. 2007;45:159-64.
54. Poredos P, Jezovnik MH. The role of inflammation in venous thromboembolism and the link between arterial and venous thrombosis. Int Angiol. 2007;26:306-11.
55. Chen CP. Syndromes, disorders and maternal risk factors associated with neural tube defects (IV). Taiwan J Obstet Gynecol. 2008;47:141-50.
56. Martínez-Frías ML. The biochemical structure and function of methylenetetrahydrofolate reductase provide the rationale to interpret the epidemiological results on the risk for infants with Down syndrome. Am J Med Genet A. 2008;146A:1477-82.
57. Rachidi M, Lopes C. Mental retardation and associated neurological dysfunctions in Down syndrome: a consequence of dysregulation in critical chromosome 21 genes and associated molecular pathways. Eur J Paediatr Neurol. 2008;12:168-82.
58. Ifergan I,AssarafYG. Molecular mechanisms of adaptation to folate deficiency. Vitam Horm. 2008;79:99-143.
59. McLean E, de Benoist B,Allen LH. Review of the magnitude of folate and vitamin B12 deficiencies worldwide. Food Nutr Bull. 2008;29(2 Suppl):S38-51.
60. Neves C, Jorge R, Barcelos A. The network of methotrexate toxicity. Acta Reumatol Port. 2009;34:11-34.
61. Romanelli P, Bouzari N. New clinical syndromes in dermatology. Semin Cutan Med Surg. 2006;25:79-86.
62. Gisondi P, Fantuzzi F, Malerba M et al. Folic acid in general medicine and dermatology. J Dermatolog Treat. 2007;18:138-46.
64. Oeffinger HC. Are survivors of acute lymphoblastic leukemia (ALL) at increased risk of cardiovascular disease? Pediatr Blood Cancer. 2008;50(2 Suppl):462-7.
65. Mato JM, Martínez-Chantar ML, Lu SC. Methionine metabolism and liver disease. Annu Rev Nutr. 2008;28:273-93.
66. Wijekoon EP, Brosnan ME, Brosnan JT. Homocysteine metabolism in diabetes. Biochem Soc Trans. 2007;35(Pt 5):1175-9.
67. Urquhart BL, House AA. Assessing plasma total homocysteine in patients with end-stage renal disease. Perit Dial Int. 2007;27:476-88.
68. Yi F, Li PL. Mechanisms of homocysteine-induced glomerular injury and sclerosis. Am J Nephrol. 2008;28:254-64.
69. Jamaluddin MS,Yang X, Wang H. Hyperhomocysteinemia, DNAmethylation and vascular disease. Clin Chem Lab Med. 2007;45:1660-6.
70. Smith BC, Denu JM. Chemical mechanisms of histone lysine and arginine modifications. Biochim Biophys Acta. 2009;1789:45-57.
71. Svedruziæ XM. Mammalian cytosine DNA methyltransferase Dnmt1: enzymatic mechanism, novel mechanism-based inhibitors, and RNA-directed DNA methylation. Curr Med Chem. 2008;15:92-106.
72. Thorne JL, Campbell MJ, Turner BM. Transcription factors, chromatin and cancer. Int J Biochem Cell Biol. 2009;41:164-75.
73. McPherson RA, Pincus MR. Henry’s Clinical Diagnosis and Management by Laboratory Methods, 21a.ed., China. Saunders-Elsevier. 2007.
74. Selhub J. Public health significance of elevated homocysteine. Food Nutr Bull. 2008;29(2 Suppl):S116-25.
75. Glushchenko AV, Jacobsen DW. Molecular targeting of proteins by L- homocysteine: mechanistic implications for vascular disease. Antioxid Redox Signal. 2007;9:1883-98.
76. Jakubowski H. The molecular basis of homocysteine thiolactone-mediated vascular disease. Clin Chem Lab Med. 2007;45:1704-16.
77. Per³a-Haján J, Twardowski T, Jakubowski H. Mechanisms of homocysteine toxicity in humans. Amino Acids. 2007;32:561-72.
78. Perna AF, Acanfora F, Luciano MG et al. Plasma protein homocysteinylation in uremia. Clin Chem Lab Med. 2007;45:1678-82.
79. Rodríguez Esparragón F, Hernández Trujillo Y, Macías Reyes A et al. Concerning the significance of paraoxonase-1 and SR-B1 genes in atherosclerosis. Rev Esp Cardiol. 2006;59:154-64.
80. van Himbergen TM, van Tits LJ, Roest M et al. The story of PON1: how an organophosphate-hydrolysing enzyme is becoming a player in cardiovascular medicine. Neth J Med. 2006;64:34-8.
81. Florentin M, Liberopoulos EN, Wierzbicki AS et al. Multiple actions of high-density lipoprotein. Curr Opin Cardiol. 2008;23:370-8.
82. Parthasarathy S, Litvinov D, Selvarajan H et al. Lipid peroxidation and decomposition—conflicting roles in plaque vulnerability and stability. Biochim Biophys Acta. 2008;1781:221-31.
83. Seo D, Goldschmidt-Clermont P. The paraoxonase gene family and atherosclerosis. Curr Atheroscler Rep. 2009;11:182-7.
84. Harasawa H. Clinical aspects of plasma platelet-activating factor- acetylhydrolase. Biochim Biophys Acta. 2006;1761:1359-72.
85. Sudhir H. Lipoprotein-associated phospholipase A2, vascular inflammation and cardiovascular risk prediction. Vasc Health Risk Manag. 2006;2:153-6.
86. Garza CA, Montori VM, McConnell JP et al. Association between lipoprotein- associated phospholipase A2 and cardiovascular disease: a systematic review. Mayo Clin Proc. 2007;82:159-65.
87. García GA, Gaitán AA, GarcíaA et al. Aspectos biomédicos de las fosfolipasas A2 en la especie humana. Med UNAB. 2008;11:14-27.
88. Brosnan JT, Jacobs RL, Stead LM et al. Methylation demand: a key determinant of homocysteine metabolism. Acta Biochim Pol. 2004;51:405-13.
89. Stead LM, Jacobs RL, Brosnan ME et al. Methylation demand and homocysteine metabolism. Adv Enzyme Regul. 2004;44:321-33.
90. Hharbanda HH. Role of transmethylation reactions in alcoholic liver disease. World J Gastroenterol. 2007;13:4947-54.
91. Mato JM, Lu SC. Role of S-adenosyl-L-methionine in liver health and injury. Hepatology. 2007;45:1306-12.
92. Purohit V, Abdelmalek MF, Barve S et al. Role of S-adenosylmethionine, folate, and betaine in the treatment of alcoholic liver disease: summary of a symposium. Am J Clin Nutr. 2007;86:14-24.
93. Ji C. Dissection of endoplasmic reticulum stress signaling in alcoholic and non-alcoholic liver injury. J Gastroenterol Hepatol. 2008;23 Suppl 1:S16- 24.
94. Lu SC, Mato JM. S-Adenosylmethionine in cell growth, apoptosis and liver cancer. J Gastroenterol Hepatol. 2008;23 Suppl 1:S73-7.
95. Bleich S, Hillemacher T. Homocysteine, alcoholism and its molecular networks. Pharmacopsychiatry. 2009;42 Suppl 1:S102-9.
96. Lubos E, Loscalzo J, Handy DE. Homocysteine and glutathione peroxidase-1.Antioxid Redox Signal. 2007;9:1923-40.
97. Heil SG, De VrieseAS, Hluijtmans LAet al. The role of hyperhomocysteinemia in nitric oxide (NO) and endothelium-derived hyperpolarizing factor (EDHF)- mediated vasodilatation. Cell Mol Biol (Noisy-le-grand). 2004;50:911-6.
98. Jin L, Burnett AL. NADPH oxidase: recent evidence for its role in erectile dysfunction. Asian J Androl. 2008;10:6-13.
99. Garcia GA, Clavijo DA, Mejía OR et al. Biología, patobiología, bioclínica y farmacoterapéutica de la di-metil-arginina asimétrica (ADMA) en la especie humana. Universitas Médica. 2006;47:335-48.
100. van Guldener C, Nanayakkara PW, Stehouwer CD. Homocysteine and asymmetric dimethylarginine (ADMA): biochemically linked but differently related to vascular disease in chronic kidney disease. Clin Chem Lab Med. 2007;45:1683-7.
101. Beaudin AE, Stover PJ. Folate-mediated one-carbon metabolism and neural tube defects: balancing genome synthesis and gene expression. Birth Defects Res C Embryo Today. 2007;81:183-203.
102. Taparia S, Gelineau-van Waes J, Rosenquist TH et al. Importance of folate- homocysteine homeostasis during early embryonic development. Clin Chem Lab Med. 2007;45:1717-27.
103. Pabinger I. Thrombophilia and its impact on pregnancy. Thromb Res. 2009;123(Suppl 3):S16-21.
104. Selvakumar P, Lakshmikuttyamma A, Dimmock JR et al. Methionine aminopeptidase 2 and cancer. Biochim Biophys Acta. 2006;1765:148-54.
105. Rosado JO, Salvador M, Bonatto D. Importance of the trans-sulfuration pathway in cancer prevention and promotion. Mol Cell Biochem. 2007;301:1-12.
106. Beetstra S, Suthers G, Dhillon V et al. Methionine-dependence phenotype in the de novo pathway in BRCA1 and BRCA2 mutation carriers with and without breast cancer. Cancer Epidemiol Biomarkers Prev. 2008;17:2565-71.
107. Durando X, Thivat E, Gimbergues P et al. Methionine dependency of cancer cells: a new therapeutic approach? Bull Cancer. 2008;95:69-76.
108. Weinstein SJ, Albanes D, Selhub J et al. One-carbon metabolism biomarkers and risk of colon and rectal cancers. Cancer Epidemiol Biomarkers Prev. 2008;17:3233-40.
109. Toohey JI. Dehydroascorbic acid as an anti-cancer agent. Cancer Lett. 2008;263:164-9.
110. Boldyrev AA, Johnson P. Homocysteine and its derivatives as possible modulators of neuronal and non-neuronal cell glutamate receptors inAlzheimer’s disease. J Alzheimers Dis. 2007;11:219-28.
111. Martignoni E, Tassorelli C, Nappi G et al. Homocysteine and Parkinson’s disease: a dangerous liaison? J Neurol Sci. 2007;257:31-7.
112. Tchantchou F, Shea TB. Folate deprivation, the methionine cycle, and Alzheimer’s disease. Vitam Horm. 2008;79:83-97.
113. Mielke MM, Xandi PP. Hematologic risk factors of vascular disease and their relation to dementia. Dement Geriatr Cogn Disord. 2006;21:335-52.
114. Román GC. Vascular dementia prevention: a risk factor analysis. Cerebrovasc Dis. 2005;20(Suppl 2):91-100.
115. Shah S, Bell RJ, Davis SR. Homocysteine, estrogen and cognitive decline. Climacteric. 2006;9:77-87.
116. Whiteman P, Hutchinson S, Handford PA. Fibrillin-1 misfolding and disease. Antioxid Redox Signal. 2006;8:338-46.
117. Lazzerini PE, Capecchi PL, Selvi E et al. Hyperhomocysteinemia: a cardio- vascular risk factor in autoimmune diseases? Lupus. 2007;16:852-62.
118. Lazzerini PE, Capecchi PL, Selvi E et al. Hyperhomocysteinemia, inflammation and autoimmunity. Autoimmun Rev. 2007;6:503-9.
119. Szekanecz X, Herekes G, Dér H et al.Accelerated atherosclerosis in rheumatoid arthritis. Ann N YAcad Sci. 2007;1108:349-58.
120. Toohey JI. Homocysteine toxicity in connective tissue: theories, old and new. Connect Tissue Res. 2008;49:57-61.
121. McLean RR, Hannan MT. B vitamins, homocysteine, and bone disease: epidemiology and pathophysiology. Curr Osteoporos Rep. 2007;5:112-9.
122. Anagnostis P, Haragiannis A, Hakafika AI et al. Atherosclerosis and osteopo- rosis: age-dependent degenerative processes or related entities? Osteoporos Int. 2009;20:197-207.
123. Huo HH, Sorond FA, Chen JH et al. The role of homocysteine in multisystem age-related problems: a systematic review. J Gerontol A Biol Sci Med Sci. 2005;60:1190-201.
124. Pamplona R, Barja G. Mitochondrial oxidative stress, aging and caloric restriction: the protein and methionine connection. Biochim Biophys Acta. 2006;1757:496-508.
125. Uthus EO, Brown-Borg HM. Methionine flux to transsulfuration is enhanced in the long living Ames dwarf mouse. Mech Ageing Dev. 2006;127:444-50.
126. Dai J, Wang X. Immunoregulatory effects of homocysteine on cardiovascular diseases. Sheng Li Xue Bao. 2007;59:585-92.
127. Duntas LH, Wartofsky L. Cardiovascular risk and subclinical hypothyroidism: focus on lipids and new emerging risk factors. What is the evidence? Thyroid. 2007;17:1075-84.
128. Mariotti S, Cambuli VM. Cardiovascular risk in elderly hypothyroid patients. Thyroid. 2007;17:1067-73.
129. Goldstein LB, Adams R, Alberts MJ et al. American Heart Association; American Stroke Association Stroke Council. Primary prevention of ischemic stroke: a guideline from the American Heart Association/American Stroke Association Stroke Council: cosponsored by the Atherosclerotic Peripheral Vascular Disease Interdisciplinary Working Group; Cardiovascular Nursing Council; Clinical Cardiology Council; Nutrition, Physical Activity, and Metabolism Council; and the Quality of Care and Outcomes Research Interdisciplinary Working Group. Circulation. 2006;113:e873-923.
130. Goldstein LB, Adams R, Alberts MJ et al. American Heart Association/ American Stroke Association Stroke Council; Atherosclerotic Peripheral Vascular Disease Interdisciplinary Working Group; Cardiovascular Nursing Council; Clinical Cardiology Council; Nutrition, Physical Activity, and Metabolism Council; Quality of Care and Outcomes Research Interdisciplinary Working Group; American Academy of Neurology. Primary prevention of ischemic stroke: a guideline from the American Heart Association/American Stroke Association Stroke Council: cosponsored by the Atherosclerotic Peripheral Vascular Disease Interdisciplinary Working Group; Cardiovascu- lar Nursing Council; Clinical Cardiology Council; Nutrition, Physical Activity, and Metabolism Council; and the Quality of Care and Outcomes Research Interdisciplinary Working Group: the American Academy of Neurology affirms the value of this guideline. Stroke 2006;37:1583-633.
131. Higdon JV, Frei B. Coffee and health: a review of recent human research. Crit Rev Food Sci Nutr. 2006;46:101-23.
132. Mueck AO, Seeger H. Biochemical markers surrogating on vascular effects of sex steroid hormones. Gynecol Endocrinol. 2006;22:163-73.
133. Gooren LJ, Giltay EJ. Review of studies of androgen treatment of female-to- male transsexuals: effects and risks of administration of androgens to females. J Sex Med. 2008;5:765-76.
134. Thomas C. Letter to the editor by X. Roblin et al., Influence of hypolipemic treatment on homocysteinemia] Rev Med Interne. 2003;24:335-6.
135. Musarrat H, Halathil D, Varughese GI. Metformin, B12 and homocysteine levels: the plausible cause or effect? J Formos Med Assoc. 2008;107:505-6.
136. Poduri A, Haur J, Thakur JS et al. Effect of ACE inhibitors and beta-blockers on homocysteine levels in essential hypertension. J Hum Hypertens. 2008;22:289-94.
137. Maron BA, Loscalzo J. The Treatment of Hyperhomocysteinemia. Annu Rev Med. 2009;60:39-54.