Initial DNA Damage and Heritable Permanent Change in Pepsinogen Isoenzyme Pattern in the Pyloric Mucosae of Rats After Short-Term Administration of N-Methyl-N′-nitro-N-nitrosoguanidine2

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Abstract
Initial DNA breakage and heritable permanent change in the pepsinogen isoenzyme pattern in the pyloric mucosae of male inbred W rats treated with N-methyl-N′ nitro-N-nitro-soguanidine (MNNG) were studied. The life-span (turnover) of pyloric gland cells, as estimated by pulse labeling, was about 10 days and was not influenced by administration of MNNG in the drinking water for 8 days. Intragastric administration of two 12-mg doses of MNNG (interval, 6 hr) induced DNA breakage in the pyloric mucosa. This breakage was detected by alkaline sucrose density gradient centrifugation and was repaired within 12 hours after the second dose of MNNG. No decrease or disappearance of pepsinogen isoenzyme 1 (Pg 1) was observed at this time, but a decrease of Pg 1 was observed in 3 of 10 rats after 10 days. However, 167 μg MNNG/ml administered in the drinking water for 8 days did not cause any DNA change detectable by alkaline sucrose density gradient centrifugation. Decrease or disappearance of Pg 1 was scarcely noticeable 4 days after the beginning of MNNG administration in the drinking water, but high incidences of MNNG were observed 2, 10, 25, 40, and 455 days after the end of MNNG administration for 8 days. Histopathologically preneoplastic changes were found only 455 days after MNNG treatment. These results indicated that 1) changes in the pepsinogen isoenzyme pattern were a response of newly formed pyloric gland cells that were derived from germ (stem) cells modified by MNNG and that these altered germ cells produced altered pyloric gland cells continuously and irreversibly at least until day 455; and 2) doses of MNNG too low to induce DNA breakage detectable in an alkaline sucrose density gradient could induce permanent alterations, which were expressed as a phenotypic change in pepsinogen isoenzymes. A change in Pg 1 was found to be a good marker of biochemical preneoplastic changes preceding such changes detectable morphologically.