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Differential Effects on Growth, Homocysteine, and Related Compounds of Two Inhibitors of S-Adenosylhomocysteine Catabolism, 3-Deazaadenosine, and 3-Deazaaristeromycin, in C3H/10T1/2 Cells¹

Clinical Pharmacology Unit, Department of Pharmacology and Toxicology, University of Bergen, Norway

The growth of nontransformed (Cl 8) and malignant (Cl 16) C3H/10T1/2 mouse embryo fibroblasts was inhibited by 3-deazaadenosine (c³Ado) (LD₅₀ = 195 µM for CI 8 and 30 µM for CI 16 cells) and 3-deazaaristeromycin (c³Ari) (LD₅₀ about 36 µM for CI 8 and 9 µM for CI 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 µM. At high concentrations (30–300 µM) 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.

¹ This work was supported by grants from The Norwegian Society for Fighting Cancer and The Norwegian Cancer Society.

² Fellow of the Norwegian Society for Fighting Cancer. To whom requests for reprints should be addressed, at Clinical Pharmacology Unit, Department of Pharmacology and Toxicology, University of Bergen, MFH-building, N-5021 Bergen, Norway.

³ Fellow of the Norwegian Cancer Society.

Received 5/ 3/88. Revised 9/21/88. Accepted 10/19/88.