S-adenosylhomocysteine toxicity in normal and adenosine kinase-deficient lymphoblasts of human origin.
The human lymphoblast line WI-L2 is subject to growth inhibition by a combination of the adenosine deaminase (ADA; adenosine aminohydrolase, EC 3.5.4.4.) inhibitor erythro-9-(2-hydroxy-3-nonyl)adenine (EHNA) and adenosine. Although adenosine-induced pyrimidine starvation appears to contribute to this effect, uridine only partially reverses adenosine toxicity in WI-L2 and not at all in strain 107, an adenosine kinase-(ATP:adenosine 5'-phosphotransferase, EC 2.7.1.20) deficient derivative of WI-L2. Treatment of both cell lines with EHNA and adenosine leads to striking elevations in intracellular S-adenosyl-L-homocysteine (AdoHcy), a potent inhibitor of S-adenosyl-L-methionine (AdoMet)-dependent methylation reactions. The methylation in vivo of both DNA and RNA is inhibited by concentrations of EHNA and adenosine that elevate intracellular AdoHcy. Addition of 100 muM L-homocysteine thiolactone to cells treated with EHNA and adenosine enhances adenosine toxicity and further elevates AdoHcy to levels approximately 60-fold higher than those obtained in the absence of this amino acid, presumably by combining with adenosine to form AdoHcy in a reaction catalyzed by S-adenosylhomocysteine hydrolase (EC 3.3.1.1). In the adenosine kinase-deficient strain 107, a combination of ADA inhibition and L-homocysteine thiolactone markedly increases intracellular AdoHcy and inhibits growth even in the absence of exogenous adenosine. These results demonstrate a form of toxicity from endogenously produced adenosine and support the view that AdoHcy, by inhibiting methylation, is a mediator of uridine-resistant adenosine toxicity in these human lymphoblast lines. Furthermore, they suggest that AdoHcy may play a role in the pathogenesis of the severe combined immunodeficiency disease found in most children with heritable ADA deficiency.
D000241:Adenosine / Q000633:toxicity*; D058892:Adenosine Deaminase Inhibitors; D000248:Adenosine Kinase / Q000172:deficiency*; D002455:Cell Division / Q000187:drug effects; D002460:Cell Line; D006710:Homocysteine / Q000031:analogs & derivatives* / Q000633:toxicity; D006801:Humans; D007783:Lactones; D008214:Lymphocytes / Q000187:drug effects / Q000378:metabolism*; D008745:Methylation; D010770:Phosphotransferases / Q000172:deficiency*; D012435:S-Adenosylhomocysteine / Q000378:metabolism / Q000633:toxicity*
D058892:Adenosine Deaminase Inhibitors; D007783:Lactones; D006710:Homocysteine; D012435:S-Adenosylhomocysteine; D010770:Phosphotransferases; D000248:Adenosine Kinase; D000241:Adenosine