MECHANISM OF ERYTHROCYTE ACCUMULATION OF METHYLATION INHIBITOR S-ADENOSYLHOMOCYSTEINE IN UREMIA

We have recently demonstrated that methyl esterification of erythrocyt e membrane proteins, a reaction involved in recognition and repair of specifically damaged proteins, is impaired in uremia. This is accompan ied by a significant increase in intracellular S-adenosylhomocysteine (AdoHcy), a potent inhibitor of methyltransferases. AdoHcy accumulatio n is normally prevented by its enzymatic hydrolysis to homocysteine (H cy) and adenosine, a reversible reaction catalyzed by AdoHcy hydrolase . To assess the contribution that Hcy offers in the elevation of AdoHc y, we measured plasma and red blood cell Hcy, AdoHcy, adenosine, and S -adenosylmethionine (AdoMet) intracellular concentrations, as well as RBC AdoHcy hydrolase specific activity, in standard hemodialysis patie nts and normal subjects. Plasma and red blood cell Hcy levels are sign ificantly higher in the dialysis group, and are positively correlated to AdoHcy levels. Adenosine and AdoMet levels, and AdoHcy hydrolase sp ecific activity are not significantly different between the two groups . The enzymatic formation of labeled AdoHcy from Hcy and tracer adenos ine appears to be significantly increased, in vitro, in erythrocytes f rom both control and uremic patients, when 50 mu M Hcy (concentration comparable to plasma levels actually found in vivo in uremic patients) is added to the incubation medium. When erythrocytes from uremic pati ents are incubated in vitro in absence of Hcy, a significant reduction of intracellular AdoHcy is observed with time compared to identical s amples incubated in presence of 50 mu M Hcy, with a T-1/2 of approxima tely 270 minutes. The results allow us to conclude that plasma and red cell Hcy levels actually found in uremia can be effectively responsib le for the intracellular accumulation of the toxic compound AdoHcy.