Reduced in vivo oxidative stress following 5-methyltetrahydrofolate supplementation in patients with early-onset thrombosis and 677TT methylenetetrahydrofolate reductase genotype

The protective role of folate in vascular disease has been related to antioxidant effects. In 45 patients with previous early-onset (at age < 50 years) thrombotic episodes and the 677TT methylenetetrahydrofolate reductase genotype, we evaluated the effects of a 28d-course (15 mg/d) of 5-methyltetrahydrofolate (MTHF) on homocysteine metabolism and on in vivo generation of 8-iso-prostaglandin F-2 alpha (8-iso-PGF(2 alpha)), a reliable marker of oxidative stress. At baseline, patients' fasting total homocysteine (tHcy) was 11.5 mu mol/1 (geometric mean) and urinary excretion of 8-iso-PGF(2 alpha) was 304 pg/mg creatinine, with the highest metabolite levels in the lowest quartile of plasma folate distribution (P < 0.05). After 5-MTHF supplementation, plasma folate levels increased approximately 13-fold (P < 0.0001 versus baseline); tHcy levels (6.7 mu mol/1, P < 0.0001) and urinary 8-iso-PGF(2 alpha) (254 pg/mg creatinine, P < 0.001) were both significantly lowered, their reduction being proportional to baseline values (r = 0.98 and r 0.77, respectively) and maximal in patients with the lowest pre-supplementation folate levels (P < 0.05). The effects on folate (P < 0.0001) and tHcy (P = 0.0004) persisted for at least up to 2 months after withdrawing 5-MTHF. In parallel with long- lasting tHcy-lowering effects, a short-course 5-MTHF supplementation reduces in vivo formation of 8-iso-PGF(2 alpha) in this population, supporting the antioxidant protective effects of folate in vascular disease.