Inhibition of Methylation by Adenosine in Adenosine Deaminase-Inhibited, Phytohemagglutinin-Stimulated Human Lymphocytes

作者: Jeffrey M. Johnston , Nicholas M. Kredich

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摘要: Adenosine toxicity was studied in phytohemagglutinin-stimulated, normal human, peripheral lymphocytes order to determine whether inhibition of S -adenosylmethionine (AdoMet)-mediated transmethylation reactions might contribute the immune defect associated with heritable deficiency enzyme adenosine deaminase (ADA). Cells were treated 20 µM erythro-9-(2-hydroxy-3-nonyl)adenine inhibit ADA and uridine prevent pyrimidine starvation known be caused by this system. The further addition 25 100 inhibited uptake radiolabeled thymidine leucine into acid precipitable material, also increased intracellular levels -adenosylhomocysteine (AdoHcy) from 3- 8-fold. formation these experiments AdoHcy, a potent inhibitor AdoMet-mediated reactions, presumably occurs through action hydrolase. Although physiologic function is hydrolyze reversibility reaction an equilibrium constant favoring synthesis allow net AdoHcy under conditions excess. Inclusion 200 L-homocysteine thiolactone our enhanced accumulation potentiated inhibitory effects on uptake. Cytotoxic concentrations significant vivo DNA methylation, process AdoMet-mediated, good correlation between effect noted. These findings indicate that cultured human at least part due resultant essential methylation reactions. relevance pathogenesis ADA-deficient patients not established but deserves consideration.

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