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 vitr o using the adenosine deaminase (ADA) inhibitor, 2'-deoxycoformycin (D CF). DCF completely inhibited ADA activity in glomeruli and protected against the development of PAN nephrosis; the 24-h urinary protein exc retion 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 epi thelial cells were protected against PAN-induced damage. Furthermore, when DCF was added to the first passage of GECs simultaneously with PA N, the adenosine triphosphate contents of remnant GECs on culture subs trata increased in a dose-dependent manner, and PA toxicity was comple tely 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 t o species in which PAN induced nephrosis. Additionally, DCF increased glomerular cyclic AMP contents, resulting from enhanced adenosine accu mulation in the pericellular space. These results indicate that the pa thogenesis 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 per icellular adenosine accumulation. Copyright (C) 1997 Elsevier Science Inc.