KINETICS OF TOTAL PLASMA HOMOCYSTEINE IN SUBJECTS WITH HYPERHOMOCYSTEINEMIA DUE TO FOLATE OR COBALAMIN DEFICIENCY

Hpperhomocysteinemia in cobalamin and folate deficiency reflects an im balance between influx and elimination of homocysteine (Hey) in plasma . We investigated the kinetics of total Hey (Hcy) in plasma after pero ral 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: 9.6-5 7.9 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 clea rance is normal and that massive export of Hey from tissues into plasm a is the major cause of hyperhomocysteinemia in cobalamin or folate de ficiency. However, the spread in AUC and plasma half-life values was l arge in hyperhomocysteinemic subjects, suggesting marked individual va riability in tHcy clearance. Plasma methionine after Hcy loading did n ot 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 H ey dose was excreted unchanged in the urine. demonstrating that urinar y Hey excretion does not explain normal tHcy plasma clearance in subje cts with impaired Hey remethylation. Our data suggest that hyperhomocy steinemia in folate and cobalamin deficiency is related to increased i nflux of Hey to plasma, and that the methionine synthase function is n ot an important determinant of elimination of Hey from plasma. The lar ge interindividual difference in Hcy clearance may be explained by var iable adaptation to impaired methionine synthase function through incr eased Hey flux through alternate metabolic pathways.