S-Adenosylhomocysteine accumulation and selective cytotoxicity in cultured T- and B-lymphocytes

J Lab Clin Med. 1982 Aug;100(2):269-78.

Abstract

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.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Adenine / analogs & derivatives
  • Adenine / pharmacology
  • Adenosine / pharmacology
  • Adenosine Deaminase Inhibitors*
  • Adenosylhomocysteinase
  • B-Lymphocytes / drug effects
  • B-Lymphocytes / metabolism*
  • Cell Division / drug effects
  • Cells, Cultured
  • Deoxyadenosines / pharmacology
  • Homocysteine / analogs & derivatives*
  • Homocysteine / pharmacology
  • Humans
  • Hydrolases / blood
  • Nucleoside Deaminases / antagonists & inhibitors*
  • S-Adenosylhomocysteine / blood*
  • T-Lymphocytes / drug effects
  • T-Lymphocytes / metabolism*

Substances

  • Adenosine Deaminase Inhibitors
  • Deoxyadenosines
  • Homocysteine
  • 9-(2-hydroxy-3-nonyl)adenine
  • S-Adenosylhomocysteine
  • homocysteine thiolactone
  • Hydrolases
  • Adenosylhomocysteinase
  • Nucleoside Deaminases
  • Adenine
  • Adenosine