Does Risk of Hyperhomocysteinemia Depend on Thiol-Disulfide Exchange Reactions of Albumin and Homocysteine?

Increased plasma concentrations of total homocysteine (tHcy; mild-moderate hyperhomocysteinemia: 15-50 μ tHcy) are considered an independent risk factor for the onset/progression of various diseases, but it is not known about how the increase in tHcy causes pathological conditions. Reduced homocysteine (HSH ∼1% of tHcy) is presumed to be toxic, unlike homocystine (∼9%) and mixed disulfide between homocysteine and albumin (HSS-ALB; homocysteine [Hcy]-albumin mixed disulfide, ∼90%). This and other notions make it difficult to explain the pathogenicity of Hcy because: (i) lowering tHcy does not improve pathological outcomes; (ii) damage due to HSH usually emerges at supraphysiological doses; and (iii) it is not known why tiny increments in plasma concentrations of HSH can be pathological.