Download PDF
Semin Vasc Med 2005; 5(2): 124-139
DOI: 10.1055/s-2005-872398
Copyright © 2005 by Thieme Medical Publishers, Inc., 333 Seventh Avenue, New York, NY 10001 USA.

Effect of Drugs on Homocysteine Concentrations

Jutta Dierkes1 , Sabine Westphal1
  • 1Institute of Clinical Chemistry and Biochemistry, University Hospital Magdeburg, Magdeburg, Germany
Further Information

Publication History

Publication Date:
27 July 2005 (online)

    Permissions and Reprints

ABSTRACT

Many studies conducted over the last two decades have shown that drug treatment for common medical conditions may have an adverse effect on plasma total homocysteine (tHcy) concentrations. The mechanism for the effects of individual drugs on tHcy concentrations is frequently unknown, as the mechanism of action of the drug may not be established, or the drug is typically administered in combination with other drugs. Some drugs are believed to alter tHcy concentrations by interfering in the metabolism of folate or vitamins B12 or B6 or by altering renal function, but the underlying mechanisms for the effects on tHcy concentrations of many drugs remains to be discovered. Several widely used drugs, such as lipid-lowering drugs (like fibrates and niacin) or oral hypoglycemic drugs (like metformin), insulin, drugs used in rheumatoid arthritis, and anticonvulsants cause elevated tHcy concentrations. Sex hormones have variable effects on tHcy levels, and N-acetylcysteine lowers tHcy. The mechanisms of action of drugs on tHcy concentrations and strategies to avoid tHcy elevation have been studied. Assuming that the association of tHcy with cardiovascular disease is causal, this article focuses on the adverse effect on tHcy levels of fibrates, statins and niacin, antihypertensive drugs, metformin, methotrexate and sulfasalazine, anticonvulsant drugs, and levodopa and reviews strategies to avoid such effects. The clinical significance, if any, of these adverse effects on plasma tHcy concentrations remains to be determined.

KEYWORDS

Homocysteine - lipid-lowering drugs - methotrexate - diuretics - metformin - antiepileptic drugs - levodopa

REFERENCES

  • 1 Ueland P M, Refsum H. Plasma homocysteine, a risk factor for vascular disease: plasma levels in health, disease, and drug therapy.  J Lab Clin Med. 1989;  114 473-501
    Google Scholar
  • 2 Desouza C, Keebler M, McNamara D B, Fonseca V. Drugs affecting homocysteine metabolism: impact on cardiovascular risk.  Drugs. 2002;  62 605-616
    PubMedGoogle Scholar
  • 3 Stergiou G S, Salgami E V. World Health Organization-International Society of Hypertension (WHO-ISH); USA Joint National Committee on Prevention, Detection, Evalutiaon, and Treatment of High Blood Pressure (JNC-7); European Soceity of Hypertension-European Society of Cardiology (ESH-ESC) . New European, American and International guidelines for hypertension management: agreement and disagreement.  Expert Rev Cardiovasc Ther. 2004;  2 359-368
    CrossrefPubMedGoogle Scholar
  • 4 Nygard O, Vollset S E, Refsum H et al.. Total plasma homocysteine and cardiovascular risk profile. The Hordaland Homocysteine Study.  JAMA. 1995;  274 1526-1533
    CrossrefPubMedGoogle Scholar
  • 5 Jacques P F, Bostom A G, Wilson P W, Rich S, Rosenberg I H, Selhub J. Determinants of plasma total homocysteine concentration in the Framingham Offspring cohort.  Am J Clin Nutr. 2001;  73 613-621
    PubMedGoogle Scholar
  • 6 Morrow L E, Grimsley E W. Long-term diuretic therapy in hypertensive patients: effects on serum homocysteine, vitamin B6, vitamin B12, and red blood cell folate concentrations.  South Med J. 1999;  92 866-870
    PubMedGoogle Scholar
  • 7 Montenero A S. Drugs producing vitamin deficiencies.  Acta Vitaminol Enzymol. 1980;  2 27-45
    PubMedGoogle Scholar
  • 8 Westphal S, Rading A, Luley C, Dierkes J. Antihypertensive treatment and homocysteine concentrations.  Metabolism. 2003;  52 261-263
    CrossrefPubMedGoogle Scholar
  • 9 Boushey C J, Beresford S A, Omenn G S, Motulsky A G. A quantitative assessment of plasma homocysteine as a risk factor for vascular disease. Probable benefits of increasing folic acid intakes.  JAMA. 1995;  274 1049-1057
    Google Scholar
  • 10 Mortality after 10 1/2 years for hypertensive participants in the Mltiple Risk Factor Intervention Trial.  Circulation. 1990;  82 1616-1628
    PubMedGoogle Scholar
  • 11 Kezdi P, Kezdi P C, Khamis H J. Diuretic induced long term hemodynamic changes in hypertension. A retrospective study in a MRFIT clinical center.  Clin Exp Hypertens A. 1992;  14 347-365
    PubMedGoogle Scholar
  • 12 Freis E D. The efficacy and safety of diuretics in treating hypertension.  Ann Intern Med. 1995;  122 223-226
    PubMedGoogle Scholar
  • 13 Korkmaz M E, Atar I, Tayfun E et al.. Effects of a beta-blocker and spironolactone on plasma homocysteine levels.  Int J Cardiol. 2003;  88 119-120
    CrossrefPubMedGoogle Scholar
  • 14 de Lorgeril M, Salen P, Paillard F, Lacan P, Richard G. Lipid-lowering drugs and homocysteine.  Lancet. 1999;  353 209-210
    PubMedGoogle Scholar
  • 15 Dierkes J, Westphal S, Luley C. Serum homocysteine increases after therapy with fenofibrate or bezafibrate.  Lancet. 1999;  354 219-220
    CrossrefPubMedGoogle Scholar
  • 16 Landray M J, Townend J N, Martin S, Martin U, Wheeler D C. Lipid-lowering drugs and homocysteine.  Lancet. 1999;  353 1974-1975
    PubMedGoogle Scholar
  • 17 Giral P, Bruckert E, Jacob N, Chapman M J, Foglietti M J, Turpin G. Homocysteine and lipid lowering agents. A comparison between atorvastatin and fenofibrate in patients with mixed hyperlipidemia.  Atherosclerosis. 2001;  154 421-427
    CrossrefPubMedGoogle Scholar
  • 18 Bissonnette R, Treacy E, Rozen R, Boucher B, Cohn J S, Genest Jr J. Fenofibrate raises plasma homocysteine levels in the fasted and fed states.  Atherosclerosis. 2001;  155 455-462
    CrossrefPubMedGoogle Scholar
  • 19 Jonkers I J, de Man F H, Onkenhout W, van der Laarse A, Smelt A H. Implication of fibrate therapy for homocysteine.  Lancet. 1999;  354 1208
    CrossrefPubMedGoogle Scholar
  • 20 Harats D, Yodfat O, Doolman R et al.. Homocysteine elevation with fibrates: is it a class effect?.  Isr Med Assoc J. 2001;  3 243-246
    PubMedGoogle Scholar
  • 21 Westphal S, Dierkes J, Luley C. Effects of fenofibrate and gemfibrozil on plasma homocysteine.  Lancet. 2001;  358 39-40
    CrossrefPubMedGoogle Scholar
  • 22 Melenovsky V, Stulc T, Kozich V et al.. Effect of folic acid on fenofibrate-induced elevation of homocysteine and cysteine.  Am Heart J. 2003;  146 110
    CrossrefPubMedGoogle Scholar
  • 23 Dierkes J, Westphal S, Kunstmann S, Banditt P, Lossner A, Luley C. Vitamin supplementation can markedly reduce the homocysteine elevation induced by fenofibrate.  Atherosclerosis. 2001;  158 161-164
    CrossrefPubMedGoogle Scholar
  • 24 Mayer Jr O, Simon J, Holubec L, Pikner R, Subrt I. Fenofibrate-induced hyperhomocysteinemia may be prevented by folate co-administration.  Eur J Clin Pharmacol. 2003;  59 367-371
    CrossrefPubMedGoogle Scholar
  • 25 Lipscombe J, Bargman J M. Fibrate-induced increase in blood urea and creatinine.  Nephrol Dial Transplant. 2001;  16 1515
    PubMedGoogle Scholar
  • 26 Broeders N, Knoop C, Antoine M, Tielemans C, Abramowicz D. Fibrate-induced increase in blood urea and creatinine: is gemfibrozil the only innocuous agent?.  Nephrol Dial Transplant. 2000;  15 1993-1999
    PubMedGoogle Scholar
  • 27 Hottelart C, El Esper N, Rose F, Achard J M, Fournier A. Fenofibrate increases creatininemia by increasing metabolic production of creatinine.  Nephron. 2002;  92 536-541
    CrossrefPubMedGoogle Scholar
  • 28 Devuyst O, Goffin E, Pirson Y, van Ypersele de Strihou C. Creatinine rise after fibrate therapy in renal graft recipients.  Lancet. 1993;  341 840
    PubMedGoogle Scholar
  • 29 Lipscombe J, Lewis G F, Cattran D, Bargman J M. Deterioration in renal function associated with fibrate therapy.  Clin Nephrol. 2001;  55 39-44
    PubMedGoogle Scholar
  • 30 Randers E, Erlandsen E J. Serum cystatin C as an endogenous marker of the renal function-a review.  Clin Chem Lab Med. 1999;  37 389-395
    CrossrefPubMedGoogle Scholar
  • 31 Hottelart C, el Esper N, Achard J M, Pruna A, Fournier A. Fenofibrate increases blood creatinine, but does not change the glomerular filtration rate in patients with mild renal insufficiency [in French].  Nephrologie. 1999;  20 41-44
    PubMedGoogle Scholar
  • 32 Deighan C J, Caslake M J, McConnell M, Boulton-Jones J M, Packard C J. Comparative effects of cerivastatin and fenofibrate on the atherogenic lipoprotein phenotype in proteinuric renal disease.  J Am Soc Nephrol. 2001;  12 341-348
    PubMedGoogle Scholar
  • 33 Brattstrom L, Lindgren A, Israelsson B, Andersson A, Hultberg B. Homocysteine and cysteine: determinants of plasma levels in middle-aged and elderly subjects.  J Intern Med. 1994;  236 633-641
    PubMedGoogle Scholar
  • 34 Dierkes J, Jeckel A, Ambrosch A, Westphal S, Luley C, Boeing H. Factors explaining the difference of total homocysteine between men and women in the European Investigation Into Cancer and Nutrition Potsdam study.  Metabolism. 2001;  50 640-645
    CrossrefPubMedGoogle Scholar
  • 35 Arnadottir M, Hultberg B, Nilsson-Ehle P, Thysell H. The effect of reduced glomerular filtration rate on plasma total homocysteine concentration.  Scand J Clin Lab Invest. 1996;  56 41-46
    PubMedGoogle Scholar
  • 36 Legendre C, Causse E, Chaput E, Salvayre R, Pineau T, Edgar A D. Fenofibrate induces a selective increase of protein-bound homocysteine in rodents: a PPARalpha-mediated effect.  Biochem Biophys Res Commun. 2002;  295 1052-1056
    CrossrefPubMedGoogle Scholar
  • 37 Luc G, Jacob N, Bouly M, Fruchart J C, Staels B, Giral P. Fenofibrate increases homocystinemia through a PPARalpha-mediated mechanism.  J Cardiovasc Pharmacol. 2004;  43 452-453
    PubMedGoogle Scholar
  • 38 Chambers J C, Ueland P M, Wright M, Dore C J, Refsum H, Kooner J S. Investigation of relationship between reduced, oxidized, and protein-bound homocysteine and vascular endothelial function in healthy human subjects.  Circ Res. 2001;  89 187-192
    PubMedGoogle Scholar
  • 39 Stulc T, Melenovsky V, Grauova B, Kozich V, Ceska R. Folate supplementation prevents plasma homocysteine increase after fenofibrate therapy.  Nutrition. 2001;  17 721-723
    CrossrefPubMedGoogle Scholar
  • 40 Lowering blood homocysteine with folic acid based supplements: meta-analysis of randomised trials. Homocysteine Lowering Trialists' Collaboration.  BMJ. 1998;  316 894-898
    PubMedGoogle Scholar
  • 41 Milionis H J, Papakostas J, Kakafika A, Chasiotis G, Seferiadis K, Elisaf M S. Comparative effects of atorvastatin, simvastatin, and fenofibrate on serum homocysteine levels in patients with primary hyperlipidemia.  J Clin Pharmacol. 2003;  43 825-830
    CrossrefPubMedGoogle Scholar
  • 42 Malik J, Melenovsky V, Wichterle D et al.. Both fenofibrate and atorvastatin improve vascular reactivity in combined hyperlipidaemia (fenofibrate versus atorvastatin trial-FAT).  Cardiovasc Res. 2001;  52 290-298
    CrossrefPubMedGoogle Scholar
  • 43 Sasaki S, Kuwahara N, Kunitomo K et al.. Effects of atorvastatin on oxidized low-density lipoprotein, low-density lipoprotein subfraction distribution, and remnant lipoprotein in patients with mixed hyperlipoproteinemia.  Am J Cardiol. 2002;  89 386-389
    CrossrefPubMedGoogle Scholar
  • 44 Haak E, Abletshauser C, Weber S et al.. Fluvastatin therapy improves microcirculation in patients with hyperlipidaemia.  Atherosclerosis. 2001;  155 395-401
    CrossrefPubMedGoogle Scholar
  • 45 Ridker P M, Shih J, Cook T J et al.. Air Force/Texas Coronary Atherosclerosis Prevention Study . (AFCAPS/TexCAPS) Investigators. Plasma homocysteine concentration, statin therapy, and the risk of first acute coronary events.  Circulation. 2002;  105 1776-1779
    CrossrefPubMedGoogle Scholar
  • 46 MacMahon M, Kirkpatrick C, Cummings C E et al.. A pilot study with simvastatin and folic acid/vitamin B12 in preparation for the Study of the Effectiveness of Additional Reductions in Cholesterol and Homocysteine (SEARCH).  Nutr Metab Cardiovasc Dis. 2000;  10 195-203
    PubMedGoogle Scholar
  • 47 Capecchi P L, Lazzerini P E, Maccherini M et al.. Pravastatin treatment-associated reduction in plasma homocysteine in heart-transplanted patients.  Transplant Proc. 2002;  34 1273-1274
    CrossrefPubMedGoogle Scholar
  • 48 Luftjohann D, Sigit J I, Locatelli S, von Bergmann K, Schmidt H H. High-dose simvastin (80 mg/day) decreases plasma concentrations of total homocyst(e)ine in patients with hypercholesteromia.  Atherosclerosis. 2001;  155 265-266
    CrossrefPubMedGoogle Scholar
  • 49 Basu T K, Mann S. Vitamin B-6 normalizes the altered sulfur amino acid status of rats fed diets containing pharmacological levels of niacin without reducing niacin's hypolipidemic effects.  J Nutr. 1997;  127 117-121
    PubMedGoogle Scholar
  • 50 Garg R, Malinow M, Pettinger M, Upson B, Hunninghake D. Niacin treatment increases plasma homocyst(e)ine levels.  Am Heart J. 1999;  138 1082-1087
    PubMedGoogle Scholar
  • 51 Wang W, Basinger A, Neese R A et al.. Effect of nicotinic acid administration on hepatic very low density lipoprotein-triglyceride production.  Am J Physiol Endocrinol Metab. 2001;  280 E540-E547
    PubMedGoogle Scholar
  • 52 Mudd S H, Poole J R. Labile methyl balances for normal humans on various dietary regimens.  Metabolism. 1975;  24 721-735
    CrossrefPubMedGoogle Scholar
  • 53 Kubova H, Folbergrova J, Mares P. Seizures induced by homocysteine in rats during ontogenesis.  Epilepsia. 1995;  36 750-756
    PubMedGoogle Scholar
  • 54 Bleich S, Degner D, Bandelow B, von Ahsen N, Ruther E, Kornhuber J. Plasma homocysteine is a predictor of alcohol withdrawal seizures.  Neuroreport. 2000;  11 2749-2752
    Google Scholar
  • 55 Ono H, Sakamoto A, Eguchi T et al.. Plasma total homocysteine concentrations in epileptic patients taking anticonvulsants.  Metabolism. 1997;  46 959-962
    CrossrefPubMedGoogle Scholar
  • 56 Schwaninger M, Ringleb P, Winter R et al.. Elevated plasma concentrations of homocysteine in antiepileptic drug treatment.  Epilepsia. 1999;  40 345-350
    PubMedGoogle Scholar
  • 57 Yoo J H, Hong S B. A common mutation in the methylenetetrahydrofolate reductase gene is a determinant of hyperhomocysteinemia in epileptic patients receiving anticonvulsants.  Metabolism. 1999;  48 1047-1051
    CrossrefPubMedGoogle Scholar
  • 58 Apeland T, Mansoor M A, Strandjord R E. Antiepileptic drugs as independent predictors of plasma total homocysteine levels.  Epilepsy Res. 2001;  47 27-35
    CrossrefPubMedGoogle Scholar
  • 59 Tamura T, Aiso K, Johnston K E, Black L, Faught E. Homocysteine, folate, vitamin B-12 and vitamin B-6 in patients receiving antiepileptic drug monotherapy.  Epilepsy Res. 2000;  40 7-15
    CrossrefPubMedGoogle Scholar
  • 60 Verrotti A, Pascarella R, Trotta D, Giuva T, Morgese G, Chiarelli F. Hyperhomocysteinemia in children treated with sodium valproate and carbamazepine.  Epilepsy Res. 2000;  41 253-257
    CrossrefPubMedGoogle Scholar
  • 61 Apeland T, Mansoor M A, Pentieva K, McNulty H, Strandjord R E. Fasting and post-methionine loading concentrations of homocysteine, vitamin B2, and vitamin B6 in patients on antiepileptic drugs.  Clin Chem. 2003;  49 1005-1008
    PubMedGoogle Scholar
  • 62 Apeland T, Mansoor M A, Pentieva K, McNulty H, Seljeflot I, Strandjord R E. The effect of B-vitamins on hyperhomocysteinemia in patients on antiepileptic drugs.  Epilepsy Res. 2002;  51 237-247
    CrossrefPubMedGoogle Scholar
  • 63 van Ede A E, Laan R FJM, Rood M J et al.. Effect of folic or folinic acid supplementation on the toxicity and efficacy of methotrexate in rheumatoid arthritis.  Arthritis Rheum. 2001;  44 1515-1524
    CrossrefPubMedGoogle Scholar
  • 64 Refsum H, Ueland P M, Kvinnsland S. Acute and long-term effects of high-dose methotrexate treatment on homocysteine in plasma and urine.  Cancer Res. 1986;  46 5385-5391
    PubMedGoogle Scholar
  • 65 Guttormsen A B, Ueland P M, Lonning P E, Mella O, Refsum H. Kinetics of plasma total homocysteine in patients receiving high-dose methotrexate therapy.  Clin Chem. 1998;  44 1987-1989
    PubMedGoogle Scholar
  • 66 Kishi S, Griener J, Cheng C et al.. Homocysteine, pharmacogenetics, and neurotoxicity in children with leukemia.  J Clin Oncol. 2003;  21 3084-3091
    CrossrefPubMedGoogle Scholar
  • 67 Krogh Jensen M, Ekelund S, Svendsen L. Folate and homocysteine status and haemolysis in patients treated with sulphasalazine for arthritis.  Scand J Clin Lab Invest. 1996;  56 421-429
    PubMedGoogle Scholar
  • 68 Haagsma C J, Blom H J, van Riel P L et al.. Influence of sulphasalazine, methotrexate, and the combination of both on plasma homocysteine concentrations in patients with rheumatoid arthritis.  Ann Rheum Dis. 1999;  58 79-84
    PubMedGoogle Scholar
  • 69 Roubenoff R, Dellaripa P, Nadeau M R et al.. Abnormal homocysteine metabolism in rheumatoid arthritis.  Arthritis Rheum. 1997;  40 718-722
    PubMedGoogle Scholar
  • 70 Hernanz A, Plaza A, Martin-Mola E, De Miguel E. Increased plasma levels of homocysteine and other thiol compounds in rheumatoid arthritis women.  Clin Biochem. 1999;  32 65-70
    PubMedGoogle Scholar
  • 71 Morgan S L, Baggott J E, Lee J Y, Alarcon G S. Folic acid supplementation prevents deficient blood folate levels and hyperhomocysteinemia during long term, low dose methotrexate therapy for rheumatoid arthritis: implications for cardiovascular disease prevention.  J Rheumatol. 1998;  25 441-446
    PubMedGoogle Scholar
  • 72 van Ede A E, Laan R F, Blom H J et al.. Homocysteine and folate status in methotrexate-treated patients with rheumatoid arthritis.  Rheumatology (Oxford). 2002;  41 658-665
    CrossrefPubMedGoogle Scholar
  • 73 Slot O. Changes in plasma homocysteine in arthritis patients starting treatment with low-dose methotrexate subsequently supplemented with folic acid.  Scand J Rheumatol. 2001;  30 305-307
    CrossrefPubMedGoogle Scholar
  • 74 Huemer M, Fodinger M, Huemer C et al.. Hyperhomocysteinemia in children with juvenile idiopathic arthritis is not influenced by methotrexate treatment and folic acid supplementation: a pilot study.  Clin Exp Rheumatol. 2003;  21 249-255
    PubMedGoogle Scholar
  • 75 Kuhn W, Roebroek R, Blom H et al.. Müller T. Elevated plasma levels of homocysteine in Parkinson's disease.  Eur Neurol. 1998;  40 225-227
    CrossrefPubMedGoogle Scholar
  • 76 Kuhn W, Roebroek R, Blom H, van Oppenraaij D, Müller T. Hyperhomocysteinemia in Parkinson's disease.  J Neurol. 1998;  245 811-812
    CrossrefPubMedGoogle Scholar
  • 77 Muller T, Werne B, Fowler B, Kuhn W. Nigral endothelial dysfunction, homocysteine, and Parkinson's disease.  Lancet. 1999;  354 126-127
    CrossrefPubMedGoogle Scholar
  • 78 Muller T, Woitalla D, Hauptmann B, Fowler B, Kuhn W. Decrease of methionine and S-adenosylmethionine and increase of homocysteine in treated patients with Parkinson's disease.  Neurosci Lett. 2001;  308 54-56
    CrossrefPubMedGoogle Scholar
  • 79 Blandini F, Fancellu R, Martignoni E et al.. Plasma homocysteine and l-dopa metabolism in patients with Parkinson disease.  Clin Chem. 2001;  47 1102-1104
    PubMedGoogle Scholar
  • 80 Muller T, Woitalla D, Fowler B, Kuhn W. 3-OMD and homocysteine plasma levels in parkinsonian patients.  J Neural Transm. 2002;  109 175-179
    CrossrefPubMedGoogle Scholar
  • 81 Miller J W, Selhub J, Nadeau M R, Thomas C A, Feldman R G, Wolf P A. Effect of L-dopa on plasma homocysteine in PD patients: relationship to B-vitamin status.  Neurology. 2003;  60 1125-1129
    CrossrefPubMedGoogle Scholar
  • 82 Ozkan S, Colak O, Kutlu C, Ertan M, Alatas O. Plasma homocysteine levels in pergolide-treated Parkinson disease patients.  Clin Neuropharmacol. 2004;  27 163-165
    PubMedGoogle Scholar
  • 83 Rogers J D, Sanchez-Saffon A, Frol A B, Diaz-Arrastia R. Elevated plasma homocysteine levels in patients treated with levodopa: association with vascular disease.  Arch Neurol. 2003;  60 59-64
    CrossrefPubMedGoogle Scholar
  • 84 O'Suilleabhain P E, Sung V, Hernandez C et al.. Elevated plasma homocysteine level in patients with Parkinson disease: motor, affective, and cognitive associations.  Arch Neurol. 2004;  61 865-868
    CrossrefPubMedGoogle Scholar
  • 85 Muller T, Renger K, Kuhn W. Levodopa-associated increase of homocysteine levels and sural axonal neurodegeneration.  Arch Neurol. 2004;  61 657-660
    CrossrefPubMedGoogle Scholar
  • 86 Kruman I I, Culmsee C, Chan S L et al.. Homocysteine elicits a DNA damage response in neurons that promotes apoptosis and hypersensitivity to excitotoxicity.  J Neurosci. 2000;  20 6920-6926
    PubMedGoogle Scholar
  • 87 Fassbender K, Mielke O, Hennerici M, Bertsch T. Plasma homocyst(e)ine concentrations in cerebrovascular disease.  Stroke. 1999;  30 2244-2245
    PubMedGoogle Scholar
  • 88 Seshadri S, Beiser A, Selhub J et al.. Plasma homocysteine as a risk factor for dementia and Alzheimer's disease.  N Engl J Med. 2002;  346 476-483
    CrossrefPubMedGoogle Scholar
  • 89 O'Suilleabhain P, Diaz-Arrastia R. Levodopa elevates homocysteine: is this a problem?.  Arch Neurol. 2004;  61 633-634
    CrossrefPubMedGoogle Scholar
  • 90 Bailey C J, Path M RC, Turner R C. Metformin.  N Engl J Med. 1996;  334 574-579
    CrossrefPubMedGoogle Scholar
  • 91 Lord J M, Flight I H, Norman R J. Metformin in polycystic ovary syndrome: systematic review and meta-analysis.  BMJ. 2003;  327 951-953
    PubMedGoogle Scholar
  • 92 Hoogeveen E K, Kostense P J, Jakobs C, Bouter L M, Heine R J, Stehouwer C D. Does metformin increase the serum total homocysteine level in non-insulin-dependent diabetes mellitus?.  J Intern Med. 1997;  242 389-394
    CrossrefPubMedGoogle Scholar
  • 93 Buysschaert M, Dramais A S, Wallemacq P E, Hermans M P. Hyperhomocysteinemia in type 2 diabetes: relationship to macroangiopathy, nephropathy, and insulin resistance.  Diabetes Care. 2000;  23 1816-1822
    PubMedGoogle Scholar
  • 94 Carlsen S M, Folling I, Grill V, Bjerve K S, Schneede J, Refsum H. Metformin increases total serum homocysteine levels in non-diabetic male patients with coronary heart disease.  Scand J Clin Lab Invest. 1997;  57 521-527
    PubMedGoogle Scholar
  • 95 Wulffele M G, Kooy A, Lehert P et al.. Effects of short-term treatment with metformin on serum concentrations of homocysteine, folate and vitamin B12 in type 2 diabetes mellitus: a randomized, placebo-controlled trial.  J Intern Med. 2003;  254 455-463
    CrossrefPubMedGoogle Scholar
  • 96 Vrbikova J, Bicikova M, Tallova J, Hill M, Starka L. Homocysteine and steroids levels in metformin treated women with polycystic ovary syndrome.  Exp Clin Endocrinol Diabetes. 2002;  110 74-76
    Article in Thieme ConnectPubMedGoogle Scholar
  • 97 Aarsand A K, Carlsen S M. Folate administration reduces circulating homocysteine levels in NIDDM patients on long-term metformin treatment.  J Intern Med. 1998;  244 169-174
    CrossrefPubMedGoogle Scholar
  • 98 Bauman W A, Shaw S, Jayatilleke E, Spungen A M, Herbert V. Increased intake of calcium reverses vitamin B12 malabsorption induced by metformin.  Diabetes Care. 2000;  23 1227-1231
    PubMedGoogle Scholar
  • 99 Andres E, Noel E, Goichot B. Metformin-associated vitamin B12 deficiency.  Arch Intern Med. 2002;  162 2251-2252
    CrossrefPubMedGoogle Scholar
  • 100 Wouters M G, Moorrees M T, van der Mooren M J et al.. Plasma homocysteine and menopausal status.  Eur J Clin Invest. 1995;  25 801-805
    PubMedGoogle Scholar
  • 101 Andersson A, Hultberg B, Brattstrom L, Isaksson A. Decreased serum homocysteine in pregnancy.  Eur J Clin Chem Clin Biochem. 1992;  30 377-379
    PubMedGoogle Scholar
  • 102 Green T J, Houghton L A, Donovan U, Gibson R S, O'Connor D L. Oral contraceptives did not affect biochemical folate indexes and homocysteine concentrations in adolescent females.  J Am Diet Assoc. 1998;  98 49-55
    CrossrefPubMedGoogle Scholar
  • 103 Morris M S, Jacques P F, Rosenberg I H et al.. Serum total homocysteine concentration is related to self-reported heart attack or stroke history among men and women in the NHANES III.  J Nutr. 2000;  130 3073-3076
    PubMedGoogle Scholar
  • 104 Steegers-Theunissen R P, Boers G H, Steegers E A, Trijbels F J, Thomas C M, Eskes T K. Effects of sub-50 oral contraceptives on homocysteine metabolism: a preliminary study.  Contraception. 1992;  45 129-139
    CrossrefPubMedGoogle Scholar
  • 105 Brattstrom L, Israelsson B, Olsson A, Andersson A, Hultberg B. Plasma homocysteine in women on oral oestrogen-containing contraceptives and in men with oestrogen-treated prostatic carcinoma.  Scand J Clin Lab Invest. 1992;  52 283-287
    PubMedGoogle Scholar
  • 106 Smolders R G, de Meer K, Kenemans P, Teerlink T, Jakobs C, van der Mooren M J. Hormone replacement influences homocysteine levels in the methionine-loading test: a randomized placebo controlled trial in postmenopausal women.  Eur J Obstet Gynecol Reprod Biol. 2004;  117 55-59
    CrossrefPubMedGoogle Scholar
  • 107 Barnabei V M, Phillips T M, Hsia J. Plasma homocysteine in women taking hormone replacement therapy: the Postmenopausal Estrogen/Progestin Interventions (PEPI) Trial.  J Womens Health Gend Based Med. 1999;  8 1167-1172
    PubMedGoogle Scholar
  • 108 Giltay E J, Verhoef P, Gooren L J, Geleijnse J M, Schouten E G, Stehouwer C D. Oral and transdermal estrogens both lower plasma total homocysteine in male-to-female transsexuals.  Atherosclerosis. 2003;  168 139-146
    CrossrefPubMedGoogle Scholar
  • 109 Giltay E J, Hoogeveen E K, Elbers J M, Gooren L J, Asscheman H, Stehouwer C D. Effects of sex steroids on plasma total homocysteine levels: a study in transsexual males and females.  J Clin Endocrinol Metab. 1998;  83 550-553
    CrossrefPubMedGoogle Scholar
  • 110 Tepel M, van der Giet M, Schwarzfeld C, Laufer U, Liermann D, Zidek W. Prevention of radiographic-contrast-agent-induced reductions in renal function by acetylcysteine.  N Engl J Med. 2000;  343 180-184
    CrossrefPubMedGoogle Scholar
  • 111 Ventura P, Panini R, Pasini M C, Scarpetta G, Salvioli G. N -Acetyl-cysteine reduces homocysteine plasma levels after single intravenous administration by increasing thiols urinary excretion.  Pharmacol Res. 1999;  40 345-350
    CrossrefPubMedGoogle Scholar
  • 112 Hultberg B, Andersson A, Masson P, Larson M, Tunek A. Plasma homocysteine and thiol compound fractions after oral administration of N-acetylcysteine.  Scand J Clin Lab Invest. 1994;  54 417-422
    CrossrefPubMedGoogle Scholar
  • 113 Wiklund O, Fager G, Andersson A, Lundstam U, Masson P, Hultberg B. N-acetylcysteine treatment lowers plasma homocysteine but not serum lipoprotein(a) levels.  Atherosclerosis. 1996;  119 99-106
    CrossrefPubMedGoogle Scholar
  • 114 Ventura P, Panini R, Abbati G, Marchetti G, Salvioli G. Urinary and plasma homocysteine and cysteine levels during prolonged oral N-acetylcysteine therapy.  Pharmacology. 2003;  68 105-114
    CrossrefPubMedGoogle Scholar
  • 115 Roes E M, Raijmakers M T, Peters W H, Steegers E A. Effects of oral N-acetylcysteine on plasma homocysteine and whole blood glutathione levels in healthy, non-pregnant women.  Clin Chem Lab Med. 2002;  40 496-498
    CrossrefPubMedGoogle Scholar
  • 116 Dierkes J, Domrose U, Ambrosch A, Bosselmann H P, Neumann K H, Luley C. Response of hyperhomocysteinemia to folic acid supplementation in patients with end-stage renal disease.  Clin Nephrol. 1999;  51 108-115
    PubMedGoogle Scholar
  • 117 Bostom A G, Shemin D, Yoburn D, Fisher D H, Nadeau M R, Selhub J. Lack of effect of oral N-acetylcysteine on the acute dialysis-related lowering of total plasma homocysteine in hemodialysis patients.  Atherosclerosis. 1996;  120 241-244
    CrossrefPubMedGoogle Scholar
  • 118 Friedman A N, Bostom A G, Laliberty P, Selhub J, Shemin D. The effect of N-acetylcysteine on plasma total homocysteine levels in hemodialysis: a randomized, controlled study.  Am J Kidney Dis. 2003;  41 442-446
    CrossrefPubMedGoogle Scholar
  • 119 Scholze A, Rinder C, Beige J, Riezler R, Zidek W, Tepel M. Acetylcysteine reduces plasma homocysteine concentration and improves pulse pressure and endothelial function in patients with end-stage renal failure.  Circulation. 2004;  109 369-374
    CrossrefPubMedGoogle Scholar
  • 120 Dierkes J, Domrose U, Westphal S et al.. Cardiac troponin T predicts mortality in patients with end-stage renal disease.  Circulation. 2000;  102 1964-1969
    PubMedGoogle Scholar
  • 121 Tepel M, van der Giet M, Statz M, Jankowski J, Zidek W. The antioxidant acetylcysteine reduces cardiovascular events in patients with end-stage renal failure: a randomized, controlled trial.  Circulation. 2003;  107 992-995
    CrossrefPubMedGoogle Scholar
  • 122 Ubbink J B, van der Merwe A, Delport R et al.. The effect of a subnormal vitamin B-6 status on homocysteine metabolism.  J Clin Invest. 1996;  98 177-184
    Google Scholar
  • 123 Smulders Y M, de Man A M, Stehouwer C D, Slaats E H. Trimethoprim and fasting plasma homocysteine.  Lancet. 1998;  352 1827-1828
    PubMedGoogle Scholar

Jutta DierkesPh.D. 

Institute of Clinical Chemistry and Biochemistry, University Hospital Magdeburg

Leipziger Str. 44, 39120 Magdeburg, Germany

      >