Role of aminothiols as a component of the plasma antioxidant system and relevance to homocysteine-mediated vascular disease

Hyperhomocysteinaemia is considered to be an independent risk factor for va scular disease. Elevated plasma homocysteine may pose an oxidative stress, leading to the development of vascular damage. A component of this effect m ay be a disturbance of the extracellular aminothiol redox state. The relati ve contributions of plasma total homocysteine (tHcy) and plasma total cyste ine (tCys) to the total antioxidant capacity (TAOC) of plasma was establish ed in subjects with normal and elevated plasma tHcy. A total of 10 subjects with severe hyperhomocysteinaemia (due to inherited metabolic defects), 13 of their heterozygous parents and 72 normal healthy subjects were recruite d to the study. The mean plasma tHcy in the patients was 91.8 mu mol/l, com pared with 13.2 mu mol/l in the parents and 14.7 mu mol/l in healthy contro l subjects. Plasma tCys and plasma TAOC were significantly lower in the sub jects with severe hyperhomocysteinaemia compared with the parents and healt hy control subjects (P < 0.05). In blood samples from subjects with a norma l tHcy, a positive correlation was observed between tCys and tHcy (P = 0.00 01). In contrast, in blood samples with tHcy <greater than or equal to> 20 mu mol/l, plasma tCys was negatively correlated with tHcy (P = 0.0001). In samples with tHcy greater than or equal to 20 mu mol/l, tHcy was inversely correlated with TAOC (P = 0.0001), whereas tCys was positively associated w ith TAOC (P = 0.0001). Multiple regression analysis revealed that tCys was the most important independent determinant of TAOC in the patient and contr ol groups when the effects of tHcy and several factors known to influence T AOC, such as urate, were taken into account. Thus hyperhomocysteinaemia may pose an oxidative stress not only through the direct cytotoxicity of homoc ysteine, but also from an associated fall in plasma cysteine.