S-Adenosylhomocysteine accumulation and selective cytotoxicity in cultured T- and B-lymphocytes.
To evaluate for selective toxicity of S-adenosylhomocysteine toward cultured lymphoblasts, cytotoxicity was correlated with S-adenosyl-L-homocysteine accumulation in cultured human B-lymphoblasts (MGL-8) and T-lymphoblasts (MOLT-4) during adenosine deaminase inhibition with EHNA. The addition of adenosine increased intracellular S-adenosylhomocysteine levels and decreased the growth of B-lymphoblasts, with an estimated ID50 of 50 micro M. These changes were enhanced by the addition of homocysteine thiolactone. The addition of deoxyadenosine, even with homocysteine thiolactone, had no effect in B-lymphoblasts. The addition of deoxyadenosine potently decreased the growth of T-lymphoblasts, with an estimated ID50 of 16 micro M, and increased intracellular S-adenosylhomocysteine concentrations. The changes were enhanced with the addition of homocysteine thiolactone. T-lymphoblasts cultured with adenosine showed only modest increases in intracellular S-adenosylhomocysteine levels but did have a substantial decrease in growth. These changes were not substantially modified by the addition of homocysteine thiolactone. S-adenosyl-L-homocysteine hydrolase activity did not correlate with cytotoxicity or S-adenosyl-L-homocysteine accumulation in B- or T-lymphoblasts. These data suggest that selective S-adenosyl-L-homocysteine accumulation and toxicity in B-lymphoblasts provide a potential mechanism for the B-lymphocyte defect in adenosine deaminase deficiency. The accumulation of S-adenosylhomocysteine in T-lymphoblasts and the associated cytotoxicity provide evidence to implicate this mechanism as contributing to the T-cell disorders in inherited or acquired adenosine deaminase deficiency.
D000225:Adenine / Q000031:analogs & derivatives / Q000494:pharmacology; D000241:Adenosine / Q000494:pharmacology; D058892:Adenosine Deaminase Inhibitors; D043383:Adenosylhomocysteinase; D001402:B-Lymphocytes / Q000187:drug effects / Q000378:metabolism*; D002455:Cell Division / Q000187:drug effects; D002478:Cells, Cultured; D003839:Deoxyadenosines / Q000494:pharmacology; D006710:Homocysteine / Q000031:analogs & derivatives* / Q000494:pharmacology; D006801:Humans; D006867:Hydrolases / Q000097:blood; D009700:Nucleoside Deaminases / Q000037:antagonists & inhibitors*; D012435:S-Adenosylhomocysteine / Q000097:blood*; D013601:T-Lymphocytes / Q000187:drug effects / Q000378:metabolism*
D058892:Adenosine Deaminase Inhibitors; D003839:Deoxyadenosines; D006710:Homocysteine; C010192:9-(2-hydroxy-3-nonyl)adenine; D012435:S-Adenosylhomocysteine; C007957:homocysteine thiolactone; D006867:Hydrolases; D043383:Adenosylhomocysteinase; D009700:Nucleoside Deaminases; D000225:Adenine; D000241:Adenosine