Differential effects on growth, homocysteine, and related compounds of two inhibitors of S-adenosylhomocysteine catabolism, 3-deazaadenosine, and 3-deazaaristeromycin, in C3H/10T1/2 cells.
The growth of nontransformed (Cl 8) and malignant (Cl 16) C3H/10T1/2 mouse embryo fibroblasts was inhibited by 3-deazaadenosine (c3Ado) (LD50 = 195 microM for Cl 8 and 30 microM for Cl 16 cells) and 3-deazaaristeromycin (c3Ari) (LD50 about 36 microM for Cl 8 and 9 microM for Cl 16 cells). Both compounds inhibited in a dose-dependent manner S-adenosylhomocysteine (AdoHcy) catabolism and homocysteine production, measured as homocysteine egress, and c3Ari was most potent in this respect. c3Ado gave rise to its congener, 3-deazaadenosylhomocysteine (c3AdoHcy). Addition of homocysteine thiolactone (Hcy-tl) to the medium enhanced AdoHcy (and c3AdoHcy) accumulation but did not affect the cell growth at concentrations of inhibitor less than 10 microM. At high concentrations (30-300 microM) both compounds were cytotoxic and decreased cell count when added during midexponential growth. When Hcy-tl was supplemented under these conditions it partly rescued the malignant cells exposed to c3Ari, did not affect the cytotoxicity of this agent towards the nontransformed cells, but greatly potentiated the cytotoxicity of c3Ado against both cell types. Differential metabolic effects were also observed in that high concentrations of c3Ado, but not c3Ari, induced build-up of c3AdoHcy and modulated cellular glutathione level. Growing cells contained the highest amount of glutathione, and in such cells c3Ado induced a significant increase in glutathione whereas the cytotoxic combination of c3Ado plus Hcy-tl decreased the amount of the reduced form. Quiescent confluent cells, which were less sensitive to the toxic effect of c3Ado, contained low glutathione, and under these conditions neither c3Ado alone nor in combination with Hcy-tl affected cellular glutathione. Remarkably, Hcy-tl alone induced an increase in glutathione in nondividing cells. These data suggest that homocysteine or some agents affecting homocysteine metabolism may modulate glutathione metabolism, but differently in dividing and nondividing cells.
Djurhuus
R
R
Department of Pharmacology and Toxicology, University of Bergen, Norway.
Svardal
A M
AM
Ueland
P M
PM
D000241:Adenosine / Q000031:analogs & derivatives* / Q000494:pharmacology; D000617:Aminoglycosides; D000818:Animals; D000900:Anti-Bacterial Agents / Q000494:pharmacology*; D002455:Cell Division / Q000187:drug effects; D002460:Cell Line; D004305:Dose-Response Relationship, Drug; D005978:Glutathione / Q000031:analogs & derivatives / Q000378:metabolism; D019803:Glutathione Disulfide; D006710:Homocysteine / Q000031:analogs & derivatives* / Q000378:metabolism*; D051379:Mice; D008809:Mice, Inbred C3H; D012435:S-Adenosylhomocysteine / Q000378:metabolism*; D014372:Tubercidin / Q000494:pharmacology*
D000617:Aminoglycosides; D000900:Anti-Bacterial Agents; C018258:3-deazaadenosine; D006710:Homocysteine; C034583:3-deazaaristeromycin; D012435:S-Adenosylhomocysteine; D005978:Glutathione; D000241:Adenosine; D014372:Tubercidin; D019803:Glutathione Disulfide