DNA damage produced by N-nitrosomethyl(2-oxopropyl)amine (MOP) in hamster and rat pancreas: a role for the liver.

Abstract

Utilizing the technique of alkaline elution analysis, the ability of N-nitrosomethyl(2-oxopropyl)amine (MOP), a potent pancreatic carcinogen, to damage pancreatic DNA in rats and hamsters was examined. Pancreatic DNA isolated from hamsters exposed for 1 h to MOP given i.p. at doses of 7-60 mg/kg showed dose-related DNA damage. A similar dose-response was observed in the pancreas of rats receiving 20-180 mg MOP/kg, suggesting that hamsters were 2-3 times more sensitive than rats. In contrast to the results obtained in vivo, functionally viable acinar cells from both rat and hamster pancreas, when exposed in vitro to levels of MOP comparable to those in vivo (20-180 micrograms/ml), failed to show dose-related DNA damage. Acinar cells from hamsters pretreated with 5,6-benzoflavone, an inducer of cytochrome P-450 activity, showed greatly enhanced drug-metabolizing capability, but again no DNA damage was observed upon exposure to MOP. Minced hamster or rat pancreas also failed to show DNA damage in response to MOP treatment. When hamsters in which hepatic blood supply was interrupted by ligation were given 60 mg/kg MOP i.v. and sacrificed 15 min later, damage to pancreatic and liver DNA was comparable to that observed in ligated controls which had received saline only. Administration of MOP to sham-operated animals led to extensive DNA damage in both pancreas and liver at 15 min. Analysis by h.p.l.c. showed an almost 2-fold increase in the amount of MOP present in the pancreases of the liver-ligated animals as compared to the sham-operated unligated animals. MOP was absent from the liver of the ligated animals. These experiments strongly suggest that DNA damage by MOP to the pancreatic acinar cells and probably to other pancreatic cell types, as well, requires metabolic activation by the liver.