1. The hypothesis was tested that the renal
xanthine oxidase system provides a source of
oxygen free radicals in
puromycin aminonucleoside and
adriamycin experimental
nephrosis by generating
uric acid from
hypoxanthine and
xanthine. 2. The concentrations in renal tissue of the putative intermediary products of
puromycin aminonucleoside metabolism,
hypoxanthine and
xanthine, and of their precursors,
adenosine and
inosine, were lower in rats treated with
puromycin aminonucleoside than in normal controls, whereas concentrations of the metabolites were normal after
adriamycin intoxication. Their daily urinary excretion was lower in the 24 h after
puromycin aminonucleoside administration compared with the baseline values and returned to near normal levels within 5 days. After
adriamycin the 24 h urinary excretion of
xanthine and
uric acid was double the baseline levels (P less than 0.001). 3. When equimolar amounts of
hypoxanthine were injected instead of
puromycin aminonucleoside, the concentration of all bases increased slightly in renal tissue and their urinary efflux was double the baseline level:
allantoin,
uric acid, the unmodified
nucleotide and
xanthine were the most represented compounds in urine. 4. The enzymatic activities relative to
xanthine oxidase (EC 1.1.3.22) and
xanthine dehydrogenase (EC 1.1.1.204) in renal tissues were unchanged 1 day after
puromycin aminonucleoside or
hypoxanthine intoxication and only moderately increased in both groups at 13 days (the time of appearance of heavy
proteinuria in the
puromycin aminonucleoside-treated group). In contrast,
xanthine oxidase and
xanthine dehydrogenase activities were higher in
adriamycin-treated rats at 1 and 15 days after the treatment (P less than 0.001). 5. Feeding rats with normoprotein diets containing
tungsten induced a marked and constant decrease of renal
xanthine oxidase and
xanthine dehydrogenase activities to 20% of the baseline values in both
puromycin aminonucleoside- and
adriamycin-treated rats. Inhibition of renal
xanthine oxidase and
xanthine dehydrogenase activities by
tungsten was associated with a marked reduction (P less than 0.001) of
proteinuria in
adriamycin-treated rats and the same occurred with
allopurinol, a specific inhibitor of
xanthine oxidase activity. In contrast,
tungsten treatment did not reduce the
proteinuria associated with
puromycin aminonucleoside, which reached a maximum 13 days after
puromycin aminonucleoside intoxication.
Hypoxanthine-treated rats were normoproteinuric after 2 months of observation. 6. These data demonstrate an activation of renal
xanthine oxidase and
xanthine dehydrogenase after
adriamycin intoxication which is relevant to the induction of
proteinuria. They also argue against the involvement of the renal
xanthine oxidase system as a source of
free radicals in
puromycin aminonucleoside nephrosis and suggest that the
nucleotide cycle is not a normal route for
puromycin aminonucleoside degradation.(ABSTRACT TRUNCATED AT 400 WORDS)