Inhibition of phospholipid methylation in isolated rat hepatocytes by analogues of adenosine and S-adenosylhomocysteine.

Phospholipid methylation in isolated hepatocytes was inhibited in the presence of 3-deazaadenosine (ID50=1.7 microM) 9-beta-D-arabinofuranosyladenine (ID50=6.0 microM), S-tubercidinylhomocysteine (ID50=30 microM), and 5'-deoxy-5'-isobutylthioadenosine (ID50=177 microM). A transient inhibitory effect was observed with adenosine, whereas S-adenosyl-L-homocysteine and Sinefungin were essentially without effect. The inhibition of phospholipid methylation by S-tubercidinylhomocysteine and 9-beta-D-arabinofuranosyladenine showed a lag-phase, whereas the effect of the other inhibitors was apparent within a few minutes. Cells exposed to 9-beta-D-arabinofuranosyladenine or 3-deazaadenosine accumulated large amounts of AdoHcy, and adenosine induced a transient increase in the AdoHcy level. In addition, 3-deazaadenosine served as a precursor for the formation of S-3-deazaadenosylhomocysteine, which accumulated rapidly in cells exposed to this agent. The inhibitory effects of 3-deazaadenosine, 9-beta-arabinofuranosyladenine and adenosine could be explained by the increase in total nucleosidylhomocysteine induced by these agents. In contrast, only a slight (less than 2-fold) increase in S-adenosyl-L-homocysteine content was observed in hepatocytes treated with 5'-deoxy-5'-isobutylthioadenosine, and this metabolic effect could not explain the inhibition of phospholipid methylation induced by this agent. None of the compounds tested reduced the amount nor the specific radioactivity of S-adenosylmethionine. Biological processes determining the inhibitory effects of adenosine, S-adenosyl-L-homocysteine and their analogues on phospholipid methylation in intact cells are discussed.