It has been generally accepted that sequential histological changes develop during the course of hepatocarcinogenesis as the precancerous lesions. However, the exact pathogenic mechanism and the relationship between these precancerous lesions and
carcinoma remain controversial. In 3'-methy1-4-dimethylaminoazobenzene(3'MeDAB)induced hepatocarcinogenesis, the intermediate metabolites produced by cytochrome P450 oxidase system of hepatocytes are thought to be the ultimate carcinogen, and
conceivably such drugs as ethanol which is also oxidized by the same hepatic oxidase system may affect the 3'-MeDAB induced hepatocarcinogenesis. The present study aimed to elucidate that the cytokinetic nature of the hepatic lesions developed by
3'-MeDAB administration and the effect of ethanol on the course of hepatocarcinogenesis.
Sprague-Dawley male rats about 180 g were used for the experiment, and divided into 8 groups according to the duration and doses of 3'-MeDAB and ethanol administered: 1. normal control, Ⅱ. 3'-MeDAB only for 6 weeks, Ⅲ. 3'-MeDAB only for 9
weeks,
Ⅳ.
3'-MeDAB with a small dose(4g/kg) of ethanol, V. 3'-MeDAB with a large dose(12g/kg) of ehtanol, Ⅳ. Ethanol pretreatment for 3 weeks followed by 3'-MeDAB plus ethanol for 9 weeks, VII. Ethanol only for 9 weeks in a small dose, VIII. Ethanol only
for 9
weeks in a large dose. Animals were sacrificed at 3, 6, 9, 12 and 15 weeks. The liver weight, the gross and microscopical changes of the liver were compared between the experimental groups. Cell kinetics of the various hepatic lesions developed
in
the
hepatocarcinogenesis was examined by applying the immunohistochemical method for bromodeoxyuridine(BrdU).
@ES The results are as follows:
@EN 1) Liver weights tended to increase gradually in the experimental groups treated with 3'-MeDAB with or without ethanol, whereas it decreased in the animals given ethanol alone.
2) The number and size of hepatic granules, nodules and masses continued to increase in the experimental groups given 3'-MeDAB with or without simultaneous ethanol administration, but in the ethanol pretreated animals, nodules or masses larger
than
5 mm
was not found after cessation of 3'-MeDAB.
3) The administration of 3'-MeDAB gave rise to the development of oval cell proliferation, adenomatous hyperplasia(AH), cholangiofibrosis(CF), atypical adenomatous hyperplasia(AAH) and carcinoma. On the other hand, the prior administration of
ethanol
caused a decreased development of AH, CF, AAH and carcinoma.
4) The oval cells appeared at portal areas as early as 3 weeks when they grow into the hepatic lobules in a pseudoglandular or cord pattern, but after 6 weeks they were seen extending along the margin of hepatic lobules or AH.
5) The BrdU labeling index of oval cell and AH were decreased following cessation of 3'-MeDAB administration, but that of CF continued to increase even after the cessation.
6) Most AAH developed after cessation of 3'-MeDAB administration, and its BrdU labeling index was higher than that of AH.
In conclusion, the oval cell proliferation and AH appear to be reversible lesions in contrast to the CF and AAH that are thought to gain assess the autonomously proliferative activity, and it is thought that the prior administration of ethanol
inhibits
the development of AH, CF, AAH and carcinoma following cessation of 3'-MeDAB.
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