Homocysteine: Canary in the Coal Mine or Hidden Threat? A Biochemical Study on the Role of Plasma Thiols

Homocysteinemia is routinely measured as a biomarker of cardiovascular risk, but its pathogenic role remains controversial because it is unclear whether—and how—interventions to lower homocysteine levels provide real benefit. In the present original study, we analyzed in detail the effects of oxidative stress, thiol-disulfide exchange reactions, and plasma thiol levels on homocysteinemia. We conducted a clinical study in a group of healthy, homogeneous individuals (n = 62) in which the different redox forms of plasma thiols and several biomarkers of oxidative stress were determined. Homocysteine was characterized by the fact that it was almost completely present as mixed protein disulfide (about 80%–85%). A strong inverse correlation was found between total homocysteine and glutathione concentrations, whereas no correlation was found between homocysteine and oxidative stress markers. The observation that oxidative stress does not affect total homocysteine levels in plasma was confirmed by in vitro treatments of human blood with a special device that allows slow delivery of oxidants. Experiments with cultured cells showed that they can release glutathione in large quantities with different kinetics over time. In addition, a strong inverse correlation between GSH and total homocysteine has been demonstrated in the plasma of humans of different ages and in mammalian species. All these data support the hypothesis that GSH, once released from cells, can trigger a series of thiol-disulfide exchange reactions leading to the cleavage of protein-bound homocysteine and the increase of free homocysteine, thus promoting its excretion. It can therefore be concluded that homocysteinemia can be regulated by the release of GSH from cells and that, consequently, total homocysteine in plasma can be considered a biomarker of cardiovascular risk without necessarily having a direct causal role. The specificity of this process must be taken into account when investigating the pathogenetic role of homocysteine.