Correspondence
Plasma Homocyst(e)ine or Homocysteine?
N Engl J Med 1995; 333:325August 3, 1995
- Article
To the Editor:
The article “Association between Plasma Homocysteine Concentrations and Extracranial Carotid-Artery Stenosis”1 and the accompanying editorial “Can Lowering Homocysteine Levels Reduce Cardiovascular Risk?”2 (Feb. 2 issue) draw attention to the increased risk of vascular disease in the presence of increased plasma concentrations of what both the article and the editorial term “homocysteine.”
The words “homocysteine” and “homocystine” were coined by du Vigneaud and coworkers, who discovered these compounds some 60 years ago, to designate, respectively, the reduced (sulfhydryl) and the oxidized (disulfide) forms of these next-higher homologues of cysteine and cystine.3 Normal human plasma contains a total concentration below 16 μM of homocysteine-derived moieties, in either sulfhydryl or disulfide form. Of these, only about 2 percent occur as the sulfhydryl; the remaining 98 percent are disulfides — i.e., homocystine itself or mixed disulfides combined with either free or protein cysteine.4 Although in the final step of their assay Selhub et al.1 did measure homocysteine, this substance was largely formed in vitro from disulfides during the analytic procedure. To term it “homocysteine” does not reflect this fact. In our opinion, the composite of homocysteine-derived moieties existing in vivo can be described concisely and conveniently by the deliberately ambiguous term “homocysteine.”
The distinction between this total quantity, homocyst(e)ine, and homocysteine itself is almost certainly of more than trivial importance, because many of the pathophysiologic effects of homocyst(e)ine may depend on the presence of the sulfhydryl group of homocysteine.5 Nor does plasma homocysteine always account for the same fraction of plasma homocyst(e)ine. In subjects with abnormally elevated concentrations of plasma homocyst(e)ine, such as occur in the homocystinurias because of deficiencies of cystathionine β-synthase or methylenetetrahydrofolate reductase, or in cobalamin deficiency, the plasma homocysteine concentration increases exponentially as a function of the homocyst(e)ine concentration, remaining as low as 2 to 5 percent until the homocyst(e)ine concentration exceeds 100 μM and reaching 10 to 25 percent at homocyst(e)ine concentrations of 150 to 400 μM. After methionine loading, the concentration of plasma homocysteine reaches a peak several hours before that of plasma homocyst(e)ine.4 As efforts are made to determine the pathophysiology of hyperhomocyst(e)inemia, it is important to be specific about which forms are elevated and to what extent.
This letter is a plea for all authors, reviewers, and editors concerned with homocyst(e)ine to use terminology that does not contravene long-established usage and that clarifies, instead of obscuring and confusing. In speech, it is difficult to distinguish “homocyst(e)ine” from “homocysteine.” An alternative we have found useful in communicating orally is to substitute “total Hcy” for homocyst(e)ine, spelling out the “Hcy.”
5 ReferencesS. Harvey Mudd, M.D.
National Institute of Mental Health, Bethesda, MD 20892Harvey L. Levy, M.D.
Children's Hospital, Boston, MA 021151
Selhub J ,Jacques PF ,Bostom AG , et al. Association between plasma homocysteine concentrations and extracranial carotid-artery stenosis. N Engl J Med 1995;332:286-291
Full Text | Web of Science | Medline2
Stampfer MJ ,Malinow MR . Can lowering homocysteine levels reduce cardiovascular risk? N Engl J Med 1995;332:328-329
Full Text | Web of Science | Medline3
Butz LW ,du Vigneaud V . The formation of a homologue of cystine by the decomposition of methionine with sulfuric acid. J Biol Chem 1932;99:135-142
Web of Science4
Mansoor MA ,Svardal AM ,Schneede J ,Veland PM . Dynamic relation between reduced, oxidized, and protein-bound homocysteine and other thiol components in plasma during methionine loading in healthy men. Clin Chem 1992;38:1316-1321
Web of Science | Medline5
Mudd SH, Levy HL, Skovby F. Disorders of transsulfuration. In: Scriber CR, Beaudet AL, Sly WS, Valle D, eds. The metabolic and molecular bases of inherited disease. 7th ed. Vol. 1. New York: McGraw-Hill, 1995:1279-327.
Author/Editor Response
The authors reply:
To the Editor: Drs. Mudd and Levy are correct to point out that the total plasma homocysteine concentration that we measured1 using the procedure of Araki and Sako2 included both reduced and oxidized or disulfide forms of homocysteine. The great preponderance of studies relating plasma homocysteine to vascular risk have measured total reduced and oxidized homocysteine similarly. The issue of the nomenclature for “homocyst(e)ine” raised by Drs. Mudd and Levy is important, not only for precision but also with regard to our incomplete knowledge of the relation of these different forms of the amino acid in the pathogenesis of the vascular lesions in vivo.
2 ReferencesJacob Selhub, Ph.D.
Andrew Bostom, M.D.
Irwin H. Rosenberg, M.D.
Department of Agriculture Human Nutrition Research Center on Aging at Tufts University, Boston, MA 021111
Selhub J ,Jacques PF ,Bostom AG , et al. Association between plasma homocysteine concentrations and extracranial carotid-artery stenosis. N Engl J Med 1995;332:286-291
Full Text | Web of Science | Medline2
Araki A ,Sako Y . Determination of free and total homocysteine in human plasma by high-performance liquid chromatography with fluorescence detection. J Chromatogr 1987;422:43-52
CrossRef | Web of Science | Medline
Author/Editor Response
We agree with Drs. Mudd and Levy. In our previous publications, we have used the proper terminology.1,2 We are grateful to Drs. Mudd and Levy for bringing this issue to the attention of Journal readers.
2 ReferencesMeir J. Stampfer, M.D., Dr.P.H.
Brigham and Women's Hospital, Boston, MA 02115M. Rene Malinow, M.D.
Oregon Regional Primate Research Center, Beaverton, OR 970061
Stampfer MJ ,Malinow MR ,Willett WC , et al. A prospective study of plasma homocyst(e)ine and risk of myocardial infarction in US physicians. JAMA 1992;268:877-881
CrossRef | Web of Science | Medline2
Malinow MR . Hyperhomocyst(e)inemia: a common and easily reversible risk factor for occlusive atherosclerosis. Circulation 1990;81:2004-2006
CrossRef | Web of Science | Medline
- Citing Articles (11)
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Dalibor Valik, Martin Radina, Jaroslav Sterba, Borivoj Vojtesek. (2004) Homocysteine: exploring its potential as a pharmacodynamic biomarker of antifolate chemotherapy. Pharmacogenomics 5:8, 1151-1162
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Valentina Esposito, Sebastiano Di Biase, Teresa Lettiero, Donato Labella, Rossella Simeone, Mariacarolina Salerno. (2004) Serum homocysteine concentrations in children with growth hormone (GH) deficiency before and after 12 months GH replacement. Clinical Endocrinology 61:5, 607-611
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Lily L Wu, James T Wu. (2002) Hyperhomocysteinemia is a risk factor for cancer and a new potential tumor marker. Clinica Chimica Acta 322:1-2, 21-28
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Brahmajee K. Nallamothu, A. Mark Fendrick, Gilbert S. Omenn. (2002) Homocyst(e)ine and Coronary Heart Disease. PharmacoEconomics 20:7, 429-442
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J. David Spence. (2001) Patients With Atherosclerotic Vascular Disease. American Journal of Cardiovascular Drugs 1:2, 85-89
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Gere Sunder-Plassmann, Andreas Floth, Manuela Födinger. (2000) Hyperhomocysteinemia in organ transplantation. Current Opinion in Urology 10:2, 87-94
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SUSAN C. GUBA, LOUIS M. FINK, VIVIAN FONSECA. (1998) Hyperhomocysteinemia and Premature Vascular Occlusive Disease. The American Journal of the Medical Sciences 315:4, 279-285
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GEORGE N. WELCH, GILBERT UPCHURCH, JOSEPH LOSCALZO. (1997) Hyperhomocyst(e)inemia and Atherothrombosis. Annals of the New York Academy of Sciences 811:1 Atheroscleros, 48-59
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