© 2000 American Heart Association, Inc.
Special Article |
Homocysteine and Its Disulfide Derivatives
A Suggested Consensus Terminology
From the Laboratory of Molecular Biology (S.H.M.), National Institute of Mental Health, Bethesda, Md; the Veterans Administration Medical Center and George Washington University (J.D.F.), Washington, DC; the LOCUS for Homocysteine and Related Vitamins (H.R., P.M.U.), Armauer Hansens hus, University of Bergen, Bergen, Norway; the Oregon Regional Primate Research Center (M.R.M.), Beaverton, and Oregon Health Sciences University, Portland; the Department of Internal Medicine (S.R.L.), University of Iowa College of Medicine, Iowa City; the Department of Cell Biology (D.W.J.), Lerner Research Institute, Cleveland Clinic Foundation, Cleveland, Ohio; the Department of Medicine (L.B.), County Hospital, Kalmar, Sweden; the Department of Biochemical Genetics (B.W.), New Children’s Hospital, Sydney, Australia; the Department of Cardiovascular Medicine (D.E.L.W.), University of New South Wales, Prince of Wales Hospital, Sydney, Australia; the Department of Pediatrics (H.J.B.), University Hospital Nijmegen, Nijmegen, Netherlands; the Division of Hematology (S.P.S., R.H.A.), University of Colorado Health Sciences Center, Denver; and the Jean Mayer USDA Human Nutrition Research Center (J.S., I.H.R.), Tufts University, Boston, Mass.
Correspondence to S. Harvey Mudd, MD, NIMH/DIRP/LMB, Bldg 36, Room 1B-08, 36 Convent Dr MSC 4034, Bethesda, MD 20892-4034. E-mail shm{at}codon.nih.gov
Key Words: homocysteine • homocystine • disulfide • hyperhomocysteinemia • tHcy
In recent years, there has been an upsurge of interest in elevation of the plasma concentration of homocysteine and closely related metabolites as an independent risk factor for cardiovascular disease (reviewed, for example, in References 1 through 31 2 3 ). Homocysteine itself is a thiol- (sulfhydryl-) containing amino acid, but in normal human plasma and other tissues, a variety of related disulfide derivatives may be present. Different authors have written about these compounds and their effects by using differing terminologies. To promote clarity of meaning and to minimize uncertainty, perhaps even confusion, it is important that each article discussing these compounds either defines explicitly the terms and/or abbreviations used or cites a prior publication in which such definitions are provided. Optimally, a more uniform consensus terminology will be developed and adopted by the field. This article describes very briefly the structures of the relevant compounds and sets forth terms and abbreviations that, it is hoped, may provide a basis for such a consensus.
The word "homocysteine" was used first by Du Vigneaud and coworkers
>65 years ago when they discovered this compound4 and
provided definitive proof that it had the structure of a thiol (ie,
sulfhydryl) 4-carbon 
-amino acid:
HSCH2CH2CH(NH2)COOH.5
The symmetrical disulfide of homocysteine was termed "homocystine,"
both names being chosen to indicate that each carbon chain of these
compounds contained 1 -CH2- group more than those
of, respectively, cysteine and cystine (already well known by that
time). Since then, homocysteine and homocystine have been the standard
names, widely accepted, and extensively used in the chemical and
biochemical literature.
Normal human plasma contains total concentrations of homocysteine and
its derivative disulfides close to 10 µmol/L, although there is
some variation due to genetic factors, age, sex, menopausal status, and
other physiological and lifestyle variables
(detailed, for example, in Refsum et al6 ). Of this total,
only 
1% to 2% occurs as the thiol, homocysteine.7 The
remaining 98% is in the form of disulfides (the
Figure
). Perhaps 75% of the total is
bound to protein through disulfide bonds with protein cysteines, mainly
in albumin, whereas the remainder occurs in non–protein-bound
forms: homocystine, homocysteine-cysteine disulfide, and more minor
amounts of other mixed disulfides, eg, homocysteine-cysteinylglycine
disulfide.7 In patients with abnormally elevated total
concentrations of these compounds, such as occur in the homocystinurias
(examples specified below), the percentage contribution of the thiol
homocysteine to the total of these forms in plasma rises, reaching 10%
to 25% as the total reaches 150 to 400
µmol/L.8
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All of the disulfides in question may be cleaved by treatment with suitable reducing agents, yielding the thiol homocysteine. Most modern methods for measuring homocysteine and its disulfides rely on such a reductive treatment, followed by either determination of the resulting homocysteine or measurement of a suitable derivative of it, so that the amount measured is the sum of any homocysteine originally present plus that originally present as a disulfide. However, for some purposes, it is important to distinguish between these forms—for example, when considering the pathophysiological importance of the individual compounds. At a minimum, when writing about them, it is essential to be clear which were measured and what forms one has in mind when mentioning metabolic, physiological, or pathophysiological effects.
We list the relevant structures in the
Table, together with definitions of each
and suggested abbreviations that may be useful.
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Comments on the Abbreviations, Their Definitions, and Their Usage
"Hcy"
In formulas and abbreviations of the International Union of Pure
and Applied Chemists–International Union of Biochemistry (IUPAC-IUB)
Joint Commission on Biochemical Nomenclature for chemical compounds,
"Hcy" is the abbreviation suggested for the structure
-SCH2CH2CH(NH2)COOH.
Examples include AdoHcy for S-adenosylhomocysteine, Hcy-Hcy
for homocystine, Hcy-Cys for homocysteine-cysteine mixed disulfide, and
so forth. On the basis of the same convention, we suggest the
abbreviation "HcyH" for the free thiol, homocysteine itself.
When used within a text, Hcy is a generic term that designates collectively not only homocysteine itself but also all compounds that will give rise to the thiol homocysteine after reductive cleavage of disulfide bonds. The latter compounds include homocystine, mixed disulfides of homocysteine with other thiols, and homocysteine moieties bound to protein by a disulfide bond. The term is useful when the particular chemical form is not known—for instance, in the statement "Hcy is a risk factor for cardiovascular disease" (but it is not certain whether HcyH, Hcy-Cys, or some other Hcy-containing form has the specified effect) or when it is not particularly important to identify the chemical form.
Use of "Hcy" may require definition of the relevant tissue preparation or sample (see the examples used with "tHcy" in the next paragraph). Equally important when relevant is the distinction between total, protein-bound, and non–protein-bound forms.
"tHcy"
This abbreviation refers to the totality of homocysteine
present after the quantitative reductive cleavage of all disulfide
bonds in a sample. As noted above for Hcy, in general, a modifying
adjective must specify the specimen source. Examples would include
plasma tHcy, serum tHcy, whole-blood tHcy, hepatocyte tHcy,
endothelial cell tHcy, urinary tHcy, and so forth. When
defined as above, tHcy does not include material bound to
protein by an amide linkage, such as may be formed by reaction of
homocysteine thiolactone with protein lysine.9 Such
compounds are resistant to the reductive cleavage used to split
disulfides.
"fHcy"
This abbreviation may be used to signify "free Hcy"
(alternatively termed "non–protein-bound Hcy" or "acid-soluble
Hcy"). In each case, the prefix to Hcy will designate homocysteine
together with its disulfide moieties other than those bound to protein.
When used, the terms "fHcy" or "free Hcy" must be defined
carefully to prevent confusion with the thiol homocysteine (because
this compound contains what is often referred to as a "free"
sulfhydryl group).
"bHcy"
This abbreviation designates bound homocysteine (ie, homocysteine
bound to protein by disulfide linkage).
Terms That May Be Useful for Clinical Purposes
Homocystinuria (NOT homocysteinuria). We recommend that the term "homocystinuria" should be used exclusively for the inborn errors of metabolism characterized by markedly elevated concentrations of plasma or serum tHcy. Examples include severe deficiencies in the activity of cystathionine ß-synthase10 or methylenetetrahydrofolate reductase11 or abnormalities in the transport or metabolism of cobalamin (B12).12 To specify these abnormalities, it is generally sufficient merely to name the defect, eg, cystathionine ß-synthase deficiency, cobalamin C disease, and so forth. Some authors may choose to include the word "homocystinuria." If that is done and a particular defect is being discussed, it is generally necessary to specify, for example, "homocystinuria due to deficient activity of cystathionine ß -synthase." Read strictly, the term "homocystinuria" implies merely the presence of some homocystine in the urine. This term was introduced in the early 1960s before sensitive quantitative assays for tHcy determination had been developed. Homocystinuria was then diagnosed by measuring Hcy in urine by using qualitative methods or by amino acid analysis that detected homocystine. In publications from the 1960s and 1970s, "homocystinuria" usually refers to the inborn errors but in some instances may reflect other conditions associated with severe elevations of tHcy, eg, vitamin B12 deficiency (see Higginbottom et al13 ).
More recently, urine from normal volunteers has been shown to contain small amounts of tHcy (some 6 µmol/24 h).14 Thus, the presence of abnormally elevated amounts of urinary homocystine in the genetic diseases in question might more accurately be termed "hyperhomocystinuria." However, the long-time use of "homocystinuria" in these situations and the frequent employment of a variety of similar terms that analogously designate abnormal elevation in urine of the compound in question—eg, glycosuria, pentosuria, and phenylketonuria—suggest that an attempt to convert "homocystinuria" to "hyperhomocystinuria" would at best be of questionable value.
Hyperhomocysteinemia. By definition, this is the presence of an abnormally elevated concentration of plasma or serum tHcy. Thus, it pertains not only to homocysteine but also to all of its disulfide derivatives; ie, it designates "total homocysteine." When and where this term is used, the relevant reference range should be defined explicitly. "Hyperhomocyst(e)inemia" and "homocyst(e)ine" are terms that have often been used as synonyms for "hyperhomocysteinemia" and for "tHcy" or "Hcy," respectively, as defined in this article. If these terms are used in the future, they should be defined specifically.
Some authors have defined the quantitative degree of hyperhomocysteinemia by use of terms such as "moderate, intermediate, and severe"15 or "mild, intermediate, and severe."16 Currently there is no agreement on the quantitative limits denoted by these terms, and it is imperative that authors using them provide the relevant concentration ranges.
Normohomocysteinemia and hypohomocysteinemia. These terms provide further descriptors of the concentration of tHcy in plasma or serum and have been used by some authors.17 18 As above, an explicit statement of the quantitative limits implied should be provided if and when these terms are used.
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S. Dayal, T. Bottiglieri, E. Arning, N. Maeda, M. R. Malinow, C. D. Sigmund, D. D. Heistad, F. M. Faraci, and S. R. Lentz Endothelial Dysfunction and Elevation of S-Adenosylhomocysteine in Cystathionine {beta}-Synthase-Deficient Mice Circ. Res., June 8, 2001; 88(11): 1203 - 1209. [Abstract] [Full Text] [PDF]
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