An adenosine deaminase inhibitor prevents puromycin aminonucleoside nephrotoxicity.
Puromycin aminonucleoside (PAN) toxicity was totally inhibited in the rat in vivo and in cultured glomerular epithelial cells (GECs) in vitro using the adenosine deaminase (ADA) inhibitor, 2'-deoxycoformycin (DCF). DCF completely inhibited ADA activity in glomeruli and protected against the development of PAN nephrosis; the 24-h urinary protein excretion of treated rats compared with controls (PAN rats) 9 days after PAN injection was 16 +/- 2 mg and 524 +/- 55 mg, respectively (p < .01). Morphological examination also demonstrated that the glomerular epithelial cells were protected against PAN-induced damage. Furthermore, when DCF was added to the first passage of GECs simultaneously with PAN, the adenosine triphosphate contents of remnant GECs on culture substrata increased in a dose-dependent manner, and PA toxicity was completely inhibited by 10(-4) M DCF. The order of ADA activity in glomeruli from various species was as follows: rat > monkey > guinea pig > dog > rabbit > mouse. High activity of ADA in the glomerulus was limited to species in which PAN induced nephrosis. Additionally, DCF increased glomerular cyclic AMP contents, resulting from enhanced adenosine accumulation in the pericellular space. These results indicate that the pathogenesis of PAN toxicity is closely related to adenosine metabolism and that ADA plays a key role in this model. Furthermore, we speculate that DCF contributes to the inhibition of reactive oxygen metabolites by decreasing the substrate of xanthine oxidase and/or increasing pericellular adenosine accumulation.
Nosaka
K
K
First Department of Internal Medicine, Faculty of Medicine, University of Tokyo, Japan.
Takahashi
T
T
Nishi
T
T
Imaki
H
H
Suzuki
T
T
Suzuki
K
K
Kurokawa
K
K
Endou
H
H
D000241:Adenosine / Q000494:pharmacology; D058892:Adenosine Deaminase Inhibitors; D000818:Animals; D000242:Cyclic AMP / Q000378:metabolism; D004285:Dogs; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D005609:Free Radicals / Q000378:metabolism; D006168:Guinea Pigs; D000882:Haplorhini; D007668:Kidney / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D007678:Kidney Glomerulus / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D008297:Male; D051379:Mice; D008854:Microscopy, Electron; D015649:Pentostatin / Q000494:pharmacology; D011692:Puromycin Aminonucleoside / Q000037:antagonists & inhibitors* / Q000633:toxicity*; D011817:Rabbits; D051381:Rats; D017207:Rats, Sprague-Dawley; D017382:Reactive Oxygen Species / Q000378:metabolism; D013045:Species Specificity
D058892:Adenosine Deaminase Inhibitors; D004791:Enzyme Inhibitors; D005609:Free Radicals; D017382:Reactive Oxygen Species; D015649:Pentostatin; D011692:Puromycin Aminonucleoside; D000242:Cyclic AMP; D000241:Adenosine