A sequential study of methapyrilene hydrochloride-induced liver carcinogenesis in male F344 rats.

Methapyrilene hydrochloride [2-[2-(dimethylamino)-ethyl)-2-thenylamino)pyridine monohydrochloride (CAS: 135-23-9)]-induced hepatocarcinogenesis was studied in male F344/NCr rats by sequential histologic, histochemical, and biologic methods. Methapyrilene hydrochloride was administered in the feed to rats at a concentration of 1,000 ppm for periods up to 89 weeks. Groups of rats were killed after 5, 10, 15, 29, 40, or 73 weeks of ingesting the carcinogen. Another group was allowed to live out their life-span. Hepatocellular eosinophilic foci and adenomas were seen after 10 and 15 weeks, respectively. Basophilic foci and adenomas were found after 29 and 40 weeks, respectively. Hepatocellular carcinomas developed in 5 of 10 rats at week 40, in 3 of 5 rats at week 73, and in 19 of 19 rats that lived out their life-span. Carcinomas arose within adenomas or as small in situ carcinomas. The histologic types included trabecular, adenocarcinoma, mixed, and solid poorly differentiated hepatocellular carcinomas. Eleven of the mixed and solid poorly differentiated carcinomas metastasized to the lung. Solid poorly differentiated hepatocellular carcinomas grew upon transplantation to the mammary fat pad of weanling F344 rats. Cholangiocarcinomas were found in 7 of 19 rats only in the life-span group. Mucous cholangiofibrosis was seen in all rats after 15 weeks. With the use of Regaud's mitochondrial stain, an increased cellular density of mitochondria was seen in some hepatocytes of peripheral and central lobular areas and in some hepatocellular carcinoma cells, but not in cells in many of the adenomas and foci. Cellular alpha-fetoprotein was found by immunoperoxidase staining in portions of hepatocellular carcinomas, but not in foci, adenomas, and nonneoplastic areas. The majority of hepatocytes in foci, adenomas, and hepatocellular carcinomas contained gamma-glutamyl transpeptidase. The findings suggest that multiple pathways may be followed in the development of methapyrilene-induced liver cancer that are similar to those found in rats exposed to many other hepatic carcinogens.