Disposition of homocysteine and S-3-deazaadenosylhomocysteine in cells exposed to 3-deazaadenosine.
The nucleoside analogue, 3-deazaadenosine (c3-Ado), serves both as a substrate and as an inhibitor of S-adenosylhomocysteine (AdoHcy) hydrolase, and the ability of this compound to induce accumulation of intracellular AdoHcy and S-3-deazaadenosylhomocysteine (c3-AdoHcy) in various cells and species has been widely documented. We here report on the effect of c3-Ado on the disposition of homocysteine (Hcy) and c3-AdoHcy in isolated rat hepatocytes and in non-transformed (Cl 8) and malignant (Cl 16) C3H/10T1/2 mouse embryo fibroblasts in culture. Both the liver cells and fibroblasts release large amounts of Hcy into the extracellular medium, whereas small amounts are retained within the cells. c3-Ado (100-300 microM) nearly completely inhibits cellular Hcy egress. Intracellular Hcy in liver cells exposed to c3-Ado is in fact increased in proportion to intracellular buildup of AdoHcy, whereas c3-Ado nearly deprives the malignant Cl 16 cells of intracellular Hcy and decreases it markedly in Cl 8 cells. Adenosine exerts a similar effect as c3-Ado on Hcy and AdoHcy in liver cells, but concentrations in the mM range are required, and the effect subsides within hours. In liver cells, c3-Ado(300 microm) induces a higher level of c3-AdoHcy than of AdoHcy. In the malignant (Cl 16) fibroblasts, c3-AdoHcy content approaches the amount of AdoHcy whereas, in the non-transformed (Cl 8) fibroblasts, relatively small amounts of c3-AdoHcy are formed. Notably, c3-AdoHcy is released from all cell types in proportion to the intracellular amount, suggesting that c3-AdoHcy is efficiently handled by the mechanism responsible for the cellular egress of nucleosidylhomocysteine. The possible role of Hcy and c3-AdoHcy in the mechanism of action of c3-Ado is discussed.
D000241:Adenosine / Q000494:pharmacology; D043383:Adenosylhomocysteinase; D000818:Animals; D005347:Fibroblasts / Q000187:drug effects / Q000378:metabolism; D006710:Homocysteine / Q000031:analogs & derivatives* / Q000378:metabolism*; D006867:Hydrolases / Q000037:antagonists & inhibitors / Q000378:metabolism; D008099:Liver / Q000187:drug effects / Q000378:metabolism; D051379:Mice; D009374:Neoplasms, Experimental / Q000378:metabolism; D011485:Protein Binding; D051381:Rats; D012263:Ribonucleosides / Q000494:pharmacology*; D012435:S-Adenosylhomocysteine / Q000031:analogs & derivatives* / Q000378:metabolism; D012436:S-Adenosylmethionine / Q000378:metabolism; D014372:Tubercidin / Q000494:pharmacology*
D012263:Ribonucleosides; C018258:3-deazaadenosine; D006710:Homocysteine; C033256:S-(3-deazaadenosyl)homocysteine; D012436:S-Adenosylmethionine; D012435:S-Adenosylhomocysteine; D006867:Hydrolases; D043383:Adenosylhomocysteinase; D000241:Adenosine; D014372:Tubercidin