DNA base modifications in renal chromatin of Wistar rats treated with a renal carcinogen, ferric nitrilotriacetate.

Ferric nitrilotriacetate (Fe-NTA) causes renal proximal tubular necrosis, a consequence of iron ion-mediated free-radical-associated damage, that finally leads to a high incidence of renal adenocarcinoma in male rats and mice. We have investigated the levels of typical hydroxyl radical-induced DNA base modifications in renal chromatin of male Wistar rats treated with a single or repeated administrations of Fe-NTA. Five pyrimidine-derived and 5 purine-derived modified DNA bases were identified and quantified by gas chromatography/mass spectrometry with selected-ion monitoring. The modified bases were 5-hydroxy-5-methylhydantoin, 5-(hydroxymethyl)uracil, 5-hydroxycytosine, thymine glycol, 5,6-dihydroxyuracil, 4,6-diamino-5-formamidopyrimidine, 8-hydroxyadenine, xanthine, 2-hydroxyadenine and 8-hydroxyguanine. The amounts of most of these compounds were significantly increased over control levels in renal chromatin of Fe-NTA-treated rats as measured 3 and 24 hr after treatment. Elevated levels of modified bases were accompanied by proximal tubular necrosis. On the 19th day, however, accumulation of modified DNA bases was not observed. Morphologically, scattered karyomegalic cells were seen in the proximal tubules, but necrosis was rarely found. Some of the identified DNA base lesions are known to be promutagenic, although others have not been investigated. Presence of modified DNA bases concomitant with necrosis and regeneration of the renal proximal tubules may be a critical step in Fe-NTA-induced carcinogenesis.