Several nucleoside analogues, some of which are potent inactivators of isolated S-adenosylhomocysteinase (AdoHcyase), were tested with respect to their effect on intracellular AdoHcyase and S-adenosylhomocysteine (AdoHcy) catabolism in intact rat hepatocytes. Among the analogues tested, 9-β-d-arabinofuranosyladenine and 9-β-d-arabinofuranosyl-3-deazaadenine were the most potent inactivators of intracellular AdoHcyase. Compounds like 2-chloroadenosine and carbocyclic adenosine are extremely efficient inactivators of the isolated enzyme, but these nucleosides exerted only a limited effect on the enzyme in intact hepatocytes. Only a moderate effect was observed with 2-chloro-3-deazaadenosine and 2′-deoxyadenosine, and a high concentration of 5′-deoxy-5′-methylthioadenosine was required to inactivate the enzyme. There was a correlation between inactivation and accumulation of AdoHcy. Carbocyclic-3-deazaadenosine caused no inactivation of AdoHcyase in liver cells but caused a massive accumulation of AdoHcy, suggesting that this analogue functions as a reversible inhibitor of the enzyme. Residual enzyme activity was observed with all the nucleoside analogues tested. The intracellular enzyme inactivated in the presence of 2′-deoxyadenosine and 9-β-d-arabinofuranosyladenine was readily recovered when the cells were transferred to fresh medium containing adenosine deaminase, but reactivation of the enzyme activity after treatment of the cells with 2-chloroadenosine and 5′-deoxy-5′-methylthioadenosine was also observed. The inactivation of intracellular enzyme induced by 2-chloro-3-deazaadenosine, 9-β-d-arabinofuranosyl-3-deazaadenine, and carbocyclic adenosine was essentially irreversible under the conditions of the experiments. Factors determining the effect of nucleoside analogues on intracellular AdoHcyase are discussed.


Supported by grants from the Norwegian Society for Fighting Cancer.

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