An analysis of multiple mechanisms of adenosine toxicity in baby hamster kidney cells.
Analysis of the response of baby hamster kidney cells to adenosine in the presence of the adenosine deaminase inhibitor erythro-9-(2-hydroxy-3-nonyl) adenine has revealed two distinct mechanisms of toxicity. The first is apparent at low concentrations of adenosine (less than 5 microM) and is dependent upon the presence of a functional adenosine kinase. The initial toxicity is abolished by uridine, is unrelated to the inhibition of ribonucleotide reductase, and is accompanied by a decrease in the size of the pyrimidine nucleotide pool. Toxicity at higher concentrations of adenosine is adenosine kinase independent and is potentiated by homocysteine thiolactone. An elevation in the intracellular level of S-adenosylhomocysteine, which was observed following treatment with higher concentrations of adenosine (greater than 10 microM), is believed to mediate toxicity at these levels. Interestingly, BHK cells were resistant to intermediate levels of adenosine. The mechanism of resistance is currently unknown, but appears unrelated to a lack of inhibition of adenosine deaminase. It is proposed that substrate inhibition of adenosine kinase may be a determinant of this property.
D000225:Adenine / Q000031:analogs & derivatives / Q000494:pharmacology; D000241:Adenosine / Q000633:toxicity*; D058892:Adenosine Deaminase Inhibitors; D000248:Adenosine Kinase / Q000378:metabolism; D000818:Animals; D002448:Cell Adhesion / Q000187:drug effects; D002460:Cell Line; D003070:Coformycin / Q000031:analogs & derivatives / Q000494:pharmacology; D004351:Drug Resistance; D004357:Drug Synergism; D006168:Guinea Pigs; D006710:Homocysteine / Q000031:analogs & derivatives / Q000494:pharmacology; D007668:Kidney / Q000187:drug effects*; D009711:Nucleotides / Q000378:metabolism; D015649:Pentostatin; D012264:Ribonucleotide Reductases / Q000378:metabolism; D012435:S-Adenosylhomocysteine / Q000378:metabolism; D014529:Uridine / Q000633:toxicity
D058892:Adenosine Deaminase Inhibitors; D009711:Nucleotides; D006710:Homocysteine; D003070:Coformycin; D015649:Pentostatin; C010192:9-(2-hydroxy-3-nonyl)adenine; D012435:S-Adenosylhomocysteine; C007957:homocysteine thiolactone; D012264:Ribonucleotide Reductases; D000248:Adenosine Kinase; D000225:Adenine; D000241:Adenosine; D014529:Uridine