Homocysteine and its disulfide derivatives: a suggested consensus terminology.

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 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 a-amino acid: HSCH2CH2CH(NH2)COOH. The symmetrical disulfide of homocysteine was termed “homocystine,” both names being chosen to indicate that each carbon chain of these compounds contained 1 -CH2group 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 mmol/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 mmol/L.8 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.