Strand breakage in rat liver DNA and its repair following administration of cyclic nitrosamines.

Abstract

Sedimentation of hepatic DNA in neutral and alkaline sucrose gradients has been used to detect double- and single-strand “breaks,” respectively, following administration of the hepatocarcinogens, nitrosomorpholine, nitrosopiperidine, and dinitrosopiperazine to rats. With each compound, the relationship between initial damage to DNA and dose and the time course of restoration of high-molecular-weight DNA (“repair”) were established. Changes in the velocity sedimentation of DNA prepared 4 hr after administration of from 1 to 100 mg/kg body weight nitrosomorpholine were observed in both alkaline and neutral sucrose gradients. The single-strand damage to DNA was not completely repaired 14 days after treatment while the double-strand breaks were more rapidly repaired. Injection of similar doses of either of the other two cyclic compounds also caused single-strand breaks in liver DNA which required at least 6 days for repair. These compounds had no effect on the velocity sedimentation of DNA on neutral sucrose gradients. High doses of the respective parent cyclic amines, morpholine, piperidine, and piperazine, did not cause strand breaks in DNA. The data are discussed with particular reference to the possibility that the cyclic nitrosamines examined may be metabolized by rat liver with the formation of species capable of alkylating DNA.