Hyperhomocysteinemia in terms of steady-state kinetics

The plasma level of homocysteine (Hcy) and its oxidized products, i.e., plasma total Hcy (tHcy), is a function of the influx rate of Hcy to plasma and the plasma tHcy clearance. In vitro experiments show that proliferating cells usually export more Hcy than stationary cells and that the Hcy export increases in response to high methionine, low folate or low cobalamin level, and to agents interfering with Hcy remethylation. Comparison between various cell types suggests that hepatocytes have a unique ability to increase the Hcy export in response to extracellular methionine, probably due to its capacity to form adenosylmethionine. Some but not all cell types have an ability to use extracellular Hcy as a methionine source. Clearance studies in healthy subjects indicate that about 1.2 mmol Hcy is supplied from the cells to plasma per 24 h, which is only about 5-10% of total Hcy formed. Comparison of area under the curves after administration of Hcy and methionine shows that about 10% of the methionine administered is released to plasma as Hcy. Notably, only a few percent of Hcy from plasma is excreted unchanged in the urine, and this shows that most tHcy in plasma is metabolized. Folate or cobalamin deficient patients have normal plasma tHcy clearance, which suggests that their elevated tHcy level is due to increased Hcy export from tissues into the plasma compartment. In contrast, the hyperhomocysteinemia in renal failure is accounted for by a marked reduction in tHcy clearance, suggesting an important role of kidney in elimination of Hcy from plasma.