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Progressive Microscopic Alterations in the Livers of Rats Fed the Hepatic Carcinogens 3'-Methyl-4-dimethylaminoazobenzene and 4'-Fluoro-4-dimethylaminoazobenzene^*

( McArdle Memorial Laboratory and Department of Pathology, University of Wisconsin Medical School, Madison 6, Wis.)

1. Rats were fed a basal diet with or without 0.058 per cent of either 3'-methyl-4-dimethyl-aminoazobenzene (3'-Me-DAB) or 4'-fluoro-4-dimethylaminoazobenzene (4'-F-DAB), and animals from all groups were selected for histological studies of their livers at frequent intervals until neoplasms were grossly evident. In order to study the reversibility of the early histological changes, another group of animals was transferred to the basal diet for the duration of the experiment after ingesting the ring-methyl dye for 5 weeks.

2. Hyaline droplets and inclusions appeared in the cytoplasm after 7 days of ingestion of either carcinogen, increased in size and number, reached a maximum when the protein-bound dye was present in the largest amounts, and then gradually disappeared as the level of protein-bound dye declined. These inclusions were predominantly peripheral when 3'-Me-DAB and central when 4'-F-DAB was fed, so that by this feature one could determine microscopically which carcinogen had been ingested.

3. Considerable proliferation of the bile ducts occurred, especially when 3'-Me-DAB was fed. The new bile duct cells were the origin of cholangio fibrosis, which persisted for as long as 98 days after the carcinogen was removed from the diet. Most of the bile duct cells disappeared between the sixth and eighth weeks. Evidence is presented which suggests that these bile duct cells were transformed into parenchymal cells.

4. The neoplasms produced by these carcinogens were very similar and resembled those produced by the less active 4-dimethylaminoazobenzene. It appears that most—if not all—of these neoplasms, regardless of their histological patterns, arise from areas of cholangiofibrosis and thus have a common pathogenesis.

^* This investigation was supported in part by research grants from the National Cancer Institute, of the National Institutes of Health, Public Health Service, and the Alexander and Margaret Stewart Trust Fund.

Received 9/29/51.