DNA Damage and Repair in Rat Tissues following Administration of Azaserine1

The mechanism of action of azaserine as a carcinogen in rats was investigated. Alkaline sucrose gradients were used to determine (a) whether pancreatic DNA is damaged by azaserine as indicated by decreased sedimentation, (b) whether the DNA of liver and kidney are similarly affected, and (c) the relative rates of DNA repair in pancreas, liver, and kidney following azaserine administration. Wistar rats, sacrificed 1 hr after azaserine at 30 mg/kg i.p., had damaged DNA in pancreas, liver, and kidney. Partial repair of DNA was apparent at 1 week. At 4 weeks the DNA sedimentation profiles were unchanged from 1 week, indicating persistent damage in all three tissues. Variable damage was observed in pancreatic DNA from animals treated with 3 and 10 mg/kg, with less damage at 3 mg/kg. Azaserine, 1 mg/kg, had a minimal effect on the pancreatic DNA of Wistar rats. All Wistar/Lewis rats given injections at 3 or 10 mg/kg and sacrificed 1 hr later exhibited a uniform response to azaserine. Damage to pancreatic DNA was extensive and similar at the two dose levels and resembled that observed in Wistar rats 1 he after azaserine, 30 mg/kg. The extent of DNA repair in pancreas, liver, and kidney in Wistar/Lewis rats 1 or 4 weeks after azaserine, 10 mg/kg, was equivalent among the tissues and comparable to that detected in Wistar rats at the same intervals following a 30-mg/kg dose. Pancreatic, liver, and kidney DNA from animals treated at 10 mg/kg and sacrificed at 9 weeks sedimented like DNA from corresponding controls, as did pancreatic and liver DNA from animals treated at 3 mg/kg and sacrificed at 4 weeks. Thus, azaserine damage in pancreas, liver, and kidney cells can be detected by sedimentation of their DNA on alkaline sucrose gradients shortly after administration of the drug. No difference in either the amount of damage sustained after a given azaserine dose or in the relative rates or extent of repair of this damage in these three tissues was detectable from their DNA sedimentation profiles obtained on alkaline sucrose gradients.