Kinetics of total plasma homocysteine in subjects with hyperhomocysteinemia due to folate or cobalamin deficiency

Hpperhomocysteinemia in cobalamin and folate deficiency reflects an imbalance between influx and elimination of homocysteine (Hey) in plasma. We investigated the kinetics of total Hey (Hcy) in plasma after peroral Hey administration in 19 volunteers with hyperhomocysteinemia ((x) over bar +/- SD: 67.1 +/- 39.5 mu mol/L; range: 23.5-142.8 mu mol/L) before and after supplementation with cobalamin and/or folate. Vitamin therapy decreased plasma tHcy to 21.8 +/- 14.1 mu mol/L (range: 9.6-57.9 mu mol/L but caused only a marginal decline in the area under the curve (AUC) by 8% and plasma half-life by 21%. Using the equations for steady-state kinetics, these data indicate that mean plasma tHcy clearance is normal and that massive export of Hey from tissues into plasma is the major cause of hyperhomocysteinemia in cobalamin or folate deficiency. However, the spread in AUC and plasma half-life values was large in hyperhomocysteinemic subjects, suggesting marked individual variability in tHcy clearance. Plasma methionine after Hcy loading did not increase before (0.9 +/- 6.8 mu mol/L) but increased normally (12.8 +/- 4.6 mu mol/L) after vitamin therapy, and the methionine response discriminated between vitamin-deficient and vitamin-replete subjects. In cobalamin- or folate-deficient subjects, only 6.5 +/- 3.0% of the Hey dose was excreted unchanged in the urine. demonstrating that urinary Hey excretion does not explain normal tHcy plasma clearance in subjects with impaired Hey remethylation. Our data suggest that hyperhomocysteinemia in folate and cobalamin deficiency is related to increased influx of Hey to plasma, and that the methionine synthase function is not an important determinant of elimination of Hey from plasma. The large interindividual difference in Hcy clearance may be explained by variable adaptation to impaired methionine synthase function through increased Hey flux through alternate metabolic pathways.