Document Detail

Inhibition of hepatocytic autophagy by adenosine, adenosine analogs and AMP.
MedLine Citation:
PMID:  9865607     Owner:  NLM     Status:  MEDLINE    
Autophagy, measured in isolated rat hepatocytes as the sequestration of electroinjected [3H]raffinose, was moderately (17%) inhibited by adenosine (0.4 mM) alone, but more strongly (85%) in the presence of the adenosine deaminase inhibitor, 2'-deoxycoformycin (50 microM), suggesting that metabolic deamination of adenosine limited its inhibitory effectiveness. The adenosine analogs, 6-methylmercaptopurine riboside and N6,N6-dimethyladenosine, inhibited autophagy by 89% and 99%, respectively, at 0.5 mM, probably reflecting the adenosine deaminase-resistance of their 6-substitutions. 5-Iodotubercidin (10 microM), an adenosine kinase inhibitor, blocked the conversion of adenosine to AMP and largely abolished the inhibitory effects of both adenosine and its analogs, indicating that AMP/nucleotide formation was required for inhibition of autophagy. Inhibition by adenosine of autophagic protein degradation, measured as the release of [14C]valine from prelabelled protein, was similarly potentiated by deoxycoformycin and prevented by iodotubercidin. Inhibition of autophagy by added AMP, ADP or ATP (0.3-1 mM) was, likewise, potentiated by deoxycoformycin and prevented by iodotubercidin, suggesting dephosphorylation to adenosine and intracellular re-phosphorylation to AMP. Suppression of autophagy by AMP may be regarded as a feedback inhibition of autophagic RNA degradation, or as an aspect of the general down-regulation of energy-requiring processes that occurs under conditions of ATP depletion, when AMP levels are high.
A L Kovács; P B Gordon; E M Grotterød; P O Seglen
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Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't    
Journal Detail:
Title:  Biological chemistry     Volume:  379     ISSN:  1431-6730     ISO Abbreviation:  Biol. Chem.     Publication Date:  1998 Nov 
Date Detail:
Created Date:  1999-03-05     Completed Date:  1999-03-05     Revised Date:  2006-11-15    
Medline Journal Info:
Nlm Unique ID:  9700112     Medline TA:  Biol Chem     Country:  GERMANY    
Other Details:
Languages:  eng     Pagination:  1341-7     Citation Subset:  IM    
Department of Cell Biology, Institute for Cancer Research, The Norwegian Radium Hospital, Montebello, Oslo.
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MeSH Terms
Adenosine / analogs & derivatives,  pharmacology*
Adenosine Deaminase / antagonists & inhibitors
Adenosine Kinase / antagonists & inhibitors
Adenosine Monophosphate / pharmacology*
Autophagy / drug effects*
Cells, Cultured
Enzyme Inhibitors / pharmacology
Liver / cytology,  drug effects*
Pentostatin / pharmacology
Rats, Wistar
Tubercidin / analogs & derivatives,  pharmacology
Reg. No./Substance:
0/Enzyme Inhibitors; 24386-93-4/5-iodotubercidin; 53910-25-1/Pentostatin; 58-61-7/Adenosine; 61-19-8/Adenosine Monophosphate; 69-33-0/Tubercidin; EC Kinase; EC Deaminase

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