Effect of 9-beta-D-arabinofuranosyladenine and erythro-9-(2-hydroxy-3-nonyl) adenine on the metabolism of S-adenosylhomocysteine, S-adenosylmethionine, and adenosine in rat liver.

The effects of arabinosyladenine, an antiviral and antitumor agent used therapeutically, on the metabolism of adenosylhomocysteine were studied in rat liver. A rapid but transient accumulation of adenosylhomocysteine and adenosylmethionine was observed after a single i.p. injection of the adenosine analogue. The extent and duration of the accumulation was increased by multiple doses of arabinosyladenine and by giving the nucleoside in combination with erythro-9-(2-hydroxy-3-nonyl)-adenine, a potent inhibitor of adenosine deaminase, which significantly increased its concentration in the liver. Hepatic adenosine concentration was also enhanced by the treatment but less dramatically. Accumulation of adenosylhomocysteine resulted from a rapid but reversible in vivo inactivation of adenosylhomocysteine hydrolase. Approximately 10% of the hydrolase activity persisted despite the inactivation treatment. After four injections with arabinosyladenine (200 mumol/kg body wt.) in combination with the adenosine deaminase inhibitor (50 mumol/kg body wt.), given at 1 h intervals, the concentration of adenosylhomocysteine was increased 30-fold and that of adenosylmethionine 5-fold as compared with the control values. The concentrations remained at that level for at least 2 h and then gradually declined to the control level. The activity of adenosylhomocysteine hydrolase stayed at the 10% level for several hours but returned to the control level within 24 h of the last injection. The results show that prolonged treatment with arabinosyladenine, especially in combination with an adenosine deaminase inhibitor, causes marked but reversible changes in methionine metabolism, resulting in the hepatic accumulation of adenosylhomocysteine to a level that is likely to interfere with biological methylation reactions. This offers an additional mechanism by which arabinosyladenine may evoke toxic effects in animal cells.