Inhibition of protein synthesis induced by adenine nucleotides requires their metabolism into adenosine.
Adenine nucleotides and adenosine inhibit the incorporation of radiolabelled leucine into proteins of isolated hepatocytes. Impairment occurred with nucleotides which can be converted into 9-beta-D-ribofuranosyladenine (adenosine) but was not observed after treatment with adenine or AMPCPP (the alpha, beta-methylene analogue of ATP). Metabolism into adenosine was further suggested by the increase in cellular ATP levels following treatment of hepatocytes with ATP, adenosine or AMPPCP (the beta, gamma-methylene ATP analogue) while AMPCPP was without any significant effect. The inhibition of protein synthesis caused by adenosine was not due to a lytic effect nor to a general disturbance in hepatic functions and was reversed when the cells were washed and transferred to a nucleoside-free medium. This impairment, however, was not coupled to the activation of adenylate cyclase, as preincubation of hepatocytes with P1 purinoceptor antagonists failed to prevent protein synthesis inhibition. In contrast, L-homocysteine enhanced the inhibitory effect of adenosine on the incorporation of radiolabelled leucine into proteins. Our results thus suggest that the inhibition of protein synthesis caused by adenine nucleotides requires their conversion into adenosine. They also indicate that the inhibitory effect of adenosine does not involve a receptor-mediated effect but may be related to an increase in S-adenosylhomocysteine content and a subsequent low level of macromolecule methylation.
Tinton
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S
Départment des Sciences Pharmaceutiques, Université Catholique de Louvain, Bruxelles, Belgium.
Buc-Calderon
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P
D000227:Adenine Nucleotides / Q000378:metabolism / Q000494:pharmacology*; D000241:Adenosine / Q000378:metabolism* / Q000494:pharmacology; D000255:Adenosine Triphosphate / Q000031:analogs & derivatives / Q000032:analysis / Q000494:pharmacology; D000818:Animals; D001692:Biological Transport / Q000187:drug effects; D002478:Cells, Cultured; D000242:Cyclic AMP / Q000032:analysis; D006710:Homocysteine / Q000494:pharmacology; D007770:L-Lactate Dehydrogenase / Q000032:analysis; D007930:Leucine / Q000378:metabolism; D008099:Liver / Q000378:metabolism; D008297:Male; D014176:Protein Biosynthesis; D058915:Purinergic P1 Receptor Antagonists; D058910:Purinergic P2 Receptor Agonists; D051381:Rats; D017208:Rats, Wistar; D018048:Receptors, Purinergic P2 / Q000378:metabolism
D000227:Adenine Nucleotides; D058915:Purinergic P1 Receptor Antagonists; D058910:Purinergic P2 Receptor Agonists; D018048:Receptors, Purinergic P2; D006710:Homocysteine; C005147:5'-adenylyl (beta,gamma-methylene)diphosphonate; C022571:adenosine 5'-O-(3-thiotriphosphate); D000255:Adenosine Triphosphate; D000242:Cyclic AMP; D007770:L-Lactate Dehydrogenase; D007930:Leucine; D000241:Adenosine; C002630:alpha,beta-methyleneadenosine 5'-triphosphate