Clinical Investigation

Kidney International (1995) 47, 247–253; doi:10.1038/ki.1995.31

Mechanism of erythrocyte accumulation of methylation inhibitor S-adenosylhomocysteine in uremia

Alessandra F Perna1, Diego Ingrosso1, Natale G De Santo1, Patrizia Galletti1 and Vincenzo Zappia1

1Chair of Nephrology/Department of Pediatrics, and Institute of Biochemistry of Macromolecules, School of Medicine, Second University of Naples, Naples, Italy

Correspondence: Alessandra F Perna MD, Cattedra di Nefrologia/Dipartimento di Pediatria, Facoltà di Medicina e Chirurgia, Seconda Università degli Studi di Napoli, via Pansini 5, Pad. 17, 80131 Napoli, Italy.

Received 18 April 1994; Revised 5 August 1994; Accepted 12 August 1994.

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Abstract

Mechanism of erythrocyte accumulation of methylation inhibitor S-adenosylhomocysteine in uremia. We have recently demonstrated that methyl esterification of erythrocyte membrane proteins, a reaction involved in recognition and repair of specifically damaged proteins, is impaired in uremia. This is accompanied by a significant increase in intracellular S-adenosylhomocysteine (AdoHcy), a potent inhibitor of methyltransferases. AdoHcy accumulation is normally prevented by its enzymatic hydrolysis to homocysteine (Hey) and adenosine, a reversible reaction catalyzed by AdoHcy hydrolase. To assess the contribution that Hey offers in the elevation of AdoHcy, we measured plasma and red blood cell Hey, AdoHcy, adenosine, and S-adenosylmethionine (AdoMet) intracellular concentrations, as well as RBC AdoHcy hydrolase specific activity, in standard hemodialysis patients and normal subjects. Plasma and red blood cell Hey levels are significantly higher in the dialysis group, and are positively correlated to AdoHcy levels. Adenosine and AdoMet levels, and AdoHcy hydrolase specific activity are not significantly different between the two groups. The enzymatic formation of labeled AdoHcy from Hey and tracer adenosine appears to be significantly increased, in vitro, in erythrocytes from both control and uremic patients, when 50 microM Hey (concentration comparable to plasma levels actually found in vivo in uremic patients) is added to the incubation medium. When erythrocytes from uremic patients are incubated in vitro in absence of Hey, a significant reduction of intracellular AdoHcy is observed with time compared to identical samples incubated in presence of 50 microM Hey, with a T1/2 of approximately 270 minutes. The results allow us to conclude that plasma and red cell Hey levels actually found in uremia can be effectively responsible for the intracellular accumulation of the toxic compound AdoHcy.

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