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 (Hcy) and adenosine, a reversible reaction catalyzed by AdoHcy hydrolase. To assess the contribution that Hcy offers in the elevation of AdoHcy, 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 patients and normal subjects. Plasma and red blood cell Hcy 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 Hcy and tracer adenosine appears to be significantly increased, in vitro, in erythrocytes from both control and uremic patients, when 50 microM Hcy (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 Hcy, a significant reduction of intracellular AdoHcy is observed with time compared to identical samples incubated in presence of 50 microM Hcy, with a T1/2 of approximately 270 minutes. The results allow us to conclude that plasma and red cell Hcy levels actually found in uremia can be effectively responsible for the intracellular accumulation of the toxic compound AdoHcy.
Perna
A F
AF
Chair of Nephrology/Department of Pediatrics, School of Medicine, Second University of Naples, Italy.
Ingrosso
D
D
De Santo
N G
NG
Galletti
P
P
Zappia
V
V
D000241:Adenosine / Q000032:analysis; D043383:Adenosylhomocysteinase; D000328:Adult; D001219:Aspartate Aminotransferases / Q000032:analysis; D004912:Erythrocytes / Q000737:chemistry / Q000378:metabolism*; D005260:Female; D006710:Homocysteine / Q000378:metabolism; D006801:Humans; D006867:Hydrolases / Q000032:analysis; D008297:Male; D008745:Methylation / Q000187:drug effects; D008875:Middle Aged; D012435:S-Adenosylhomocysteine / Q000378:metabolism* / Q000494:pharmacology; D012436:S-Adenosylmethionine / Q000032:analysis; D014511:Uremia / Q000097:blood*
D006710:Homocysteine; D012436:S-Adenosylmethionine; D012435:S-Adenosylhomocysteine; D001219:Aspartate Aminotransferases; D006867:Hydrolases; D043383:Adenosylhomocysteinase; D000241:Adenosine