Reversible nephrotoxicity of onconase and effect of lysine pH on renal onconase uptake.
OBJECTIVE
To examine the histopathology of the kidney in mice following repeated injections of the antitumor drug onconase, and to determine whether lysine, which reportedly blocks kidney uptake of other basic proteins, blocks the high renal uptake of onconase.


METHODS
Mice received repeated intraperitoneal onconase injections over 3 weeks. Kidneys were examined by light microscopy after 1 week, 3 weeks, and 5 weeks (2 weeks after cessation of injections) and compared to kidneys from animals receiving a similar schedule of PBS injections. Renal uptake of radioiodinated onconase was measured in animals receiving intraperitoneal injections of lysine solutions of acidic and neutral pH given at -30, 0 and + 5 min relative to intravenous onconase injection. Renal onconase uptake was also measured in animals made metabolically acidotic by ingestion of ammonium chloride, arginine chloride or lysine dihydrochloride from the drinking water.


RESULTS
Onconase caused acute moderate multifocal proximal renal tubular necrosis, and this toxicity was reversed by 2 weeks after drug withdrawal. Intraperitoneal injections of lysine dihydrochloride in PBS (pH 1.5) reduced renal onconase uptake at 15 min from 67.9+/-13.4% to 17.0+/-3.8% of the injected dose without affecting the plasma concentration and also reduced the fraction of degraded onconase in the urine. However, neutral solutions of lysine dihydrochloride at pH 7.4 or lysine acetate at pH 7.1 were ineffective at blocking renal onconase uptake. Furthermore, renal onconase uptake was minimally or not affected by a state of metabolic acidosis.


CONCLUSIONS
Proximal tubular toxicity of onconase was reversible. Renal onconase uptake was blocked by lysine at pH 1.5 but not at neutral pH.
Biochemistry Section, Surgical Neurology Branch, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD 20892, USA.
V M
VM
Vasandani
J A
JA
Burris
C
C
Sung
D000138:Acidosis / Q000378:metabolism; D000818:Animals; D000970:Antineoplastic Agents / Q000633:toxicity*; D004527:Egg Proteins / Q000493:pharmacokinetics / Q000633:toxicity*; D005260:Female; D006863:Hydrogen-Ion Concentration; D007668:Kidney / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D008239:Lysine / Q000494:pharmacology*; D051379:Mice; D008807:Mice, Inbred BALB C; D012260:Ribonucleases / Q000493:pharmacokinetics / Q000633:toxicity*
D000970:Antineoplastic Agents; D004527:Egg Proteins; D012260:Ribonucleases; D008239:Lysine; C058703:ranpirnase