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 Hey to plasma and the plasma tHcy clearance. In vitro experiments show that p roliferating cells usually export more Hcy than stationary cells and t hat the Hcy export increases in response to high methionine, low folat e or low cobalamin level, and to agents interfering with Hcy remethyla tion. Comparison between various cell types suggests that hepatocytes have a unique ability to increase the Hcy export in response to extrac ellular methionine, probably due to its capacity to form adenosylmethi onine. Some but not all cell types have an ability to use extracellula r Hey as a methionine source. Clearance studies in healthy subjects in dicate that about 1.2 mmol Hey is supplied from the cells to plasma pe r 24 h, which is only about 5-10% of total Hcy formed. Comparison of a rea 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 Hey from plasma is excreted uncha nged in the urine, and this shows that most tHcy in plasma is metaboli zed. Folate or cobalamin deficient patients have normal plasma tHcy cl earance, which suggests that their elevated tHcy level is due to incre ased Hey export from tissues into the plasma compartment. In contrast, the hyperhomocysteinemia in renal failure is accounted for by a marke d reduction in tHcy clearance, suggesting an important role of kidney in elimination of Hcy from plasma.