Some methylated adenosine derivatives, most notably 6-dimethylaminopurine riboside and puromycin aminonucleoside, have been shown to inhibit the autophagic/lysosomal pathway of endogenous protein degradation in isolated rat hepatocytes [ 11. The mechanism of action of these methylaminopurines is not known. One possibility is that they might exert their effect by preventing the first reaction in the autophagic sequence, i.e., the sequestration of cytoplasmic material into autophagosomes [2], as do the amino acids [3-61. Another possibility is that the purines might interfere with the further processing of the autophagosomes, including their fusion with lysosomes, as seems to be the case with most other degradation inhibitors [7]. To distinguish between these two possibilities, we have undertaken a correlated biochemical and morphometric analysis of the effects of several adenine and adenosine derivatives. The results indicate that the methylated aminopurines inhibit endogenous protein degradation at the level of autophagic sequestration.
