3-Deazaadenosine. S-adenosylhomocysteine hydrolase-independent mechanism of action in mouse lymphocytes.

3-Deazaadenosine (c3Ado) inhibits the ability of specifically sensitized mouse lymphocytes to lyse tumor cells, and this effect of c3Ado on immune function is accompanied by a buildup of both S-adenosylhomocysteine (AdoHcy) and S-3-deazaadenosylhomocysteine (c3AdoHcy) within the lymphocytes (Zimmerman, T. P., Wolberg, G., and Duncan, G. S. (1978) Proc. Natl. Acad. Sci. U.S.A. 75, 6220-6224). Several types of evidence have now been obtained which indicate that neither of these latter two biochemical events contributes to this biological activity of c3Ado. First, periodate-oxidized adenosine (Adox) and 3-deaza(+/-)aristeromycin, two compounds which are not inhibitory to this lymphocyte function, were both more effective than c3Ado in elevating lymphocyte AdoHcy levels and in inhibiting protein carboxymethylation within these cells. Second, pretreatment of lymphocytes with Adox (to inhibit AdoHcy hydrolase) prevented the metabolic formation of c3AdoHcy during subsequent incubation of the cells with c3Ado without diminishment of the biological activity of c3Ado. Third, the lymphocyte buildup of c3AdoHcy exhibited a concentration dependence upon c3Ado which was biphasic and greatly dissimilar to that for the inhibition of lymphocyte function by c3Ado. These results are not compatible with the widely held view that c3Ado, as a single agent, affects various cellular functions as a consequence of elevations in intracellular AdoHcy and/or c3AdoHcy and suggest that c3Ado inhibits this particular lymphocyte function by an unknown mechanism which is independent of the interaction of c3Ado with AdoHcy hydrolase. During this study, it was found that pretreatment of lymphocytes with Adox prevented the potentiation by homocysteine of this immunoinhibitory activity of c3Ado and reduced the biological effect of the c3Ado/homocysteine combination to that observed with c3Ado alone. This result indicates that the ability of homocysteine to potentiate this biological activity of c3Ado requires the metabolic formation of c3AdoHcy catalyzed by AdoHcy hydrolase.