Persistence of DNA damage in rat pancreas following administration of three carcinogens and/or mutagens

Abstract

Alkaline sucrose gradients were used to detect and follow the persistence of DNA damage in pancreas and liver of Wistar and Wistar/Lewis rats after i.p. injection of azaserine, N δ-( N-methyl- N-nitroso-carbamyl)-L-ornithine (MNCO) or neutral red. The results were compared with the mutagenicity and carcinogenicity of each compound. Damaged DNA was present in pancreas 1 h after administration of azaserine (10 mg/kg), a pancreatic and liver carcinogen, and damage persisted in both pancreas and liver longer than a week. More extensive damage to pancreatic and liver DNA was detectable 1 week following either 6 weeks or 6 months of weekly azaserine injections than was detectable 1 week after a single injection. Damage to pancreatic DNA was detected in rats 1 h after treatment with the pancreatic carcinogen MNCO (72 or 218 mg/kg). Pancreatic DNA damage was not apparent 1 week after MNCO, 72 mg/kg, but was detectable 1 week after 218 mg/kg. Significant pancreatic DNA damage was detected 1 week after 6 weeks or 6 months of weekly MNCO injections, 72 mg/kg. Damage to liver DNA was not detectable at either 72 or 218 mg/kg whether administered once or weekly in the above protocols. One hour following injection of neutral red, 96 mg/kg, DNA damage was present in pancreas and liver, but at 1 week no damaged DNA was apparent in either tissue. Limited DNA damage was detectable in liver but not in pancreas 1 week following a toxic dose of neutral red, 288 mg/kg. Persistent DNA damage was also detectable in liver but not in pancreas after 6 weekly injections of neutral red, 96 mg/kg. The results indicate that relative persistence of DNA damage may be an accurate indication of the organotropic carcinogenic potential of azaserine, MNCO and neutral red administered at non-toxic dose levels.