Modification of the development of N-nitrosomorpholine-induced hepatic lesions by 2-acetylaminofluorene, phenobarbital and 4,4′ - diaminodiphenylmethane: a sequential histological and histochemical analysis

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Abstract
The effects of 2-acetylaminofluorene (2-AAF), sodium phenobarbital (PB) and 4,4′ -diaminodiphenylmethane (DDPM) on the developmental sequence of N-nitrosomorpholine (NNM) induced changes in the rat liver was investigated using a histological, histochemical and morpho-metric approach. Male Sprague-Dawley rats were treated with NNM for 3 weeks, maintained on basal diet for 1 week and then fed on diets containing either 0.005% 2-AAF, 0.05% PB, 0.08% DDPM or, as carcinogen controls, no addition (basal diet, BD) for a further 48 weeks. Control and experimental groups were sacrificed at weeks 4, 16, 28, 40 and 52 of the investigation. The incidence of the hepatocellular carcinomas observed at weeks 40 and 52 was markedly enhanced by 2-AAF treatment and slightly increased after PB administration. 2-AAF also exerted a positive influence on the development of angiosarcomas, benign hemangioendo-theliomas and cystic cholangiomas. DDPM did not show clear effects on the development of liver cell carcinoma but enhanced the induction of cholangiofibromas, cholangiofibrosis and, very markedly, spongiosis hepatis. No neoplastic lesions were observed in animals treated with 2-AAF, PB or DDPM without prior application of NNM. Morphometric analysis of enzyme-altered foci revealed contrasting effects of 2-AAF, PB and DDPM, not only on number and size of lesion but also on their histochemical phenotype. Thus whilst 2-AAF administration was primarily linked with increase in number of lesions, PB appeared to stabilise their phenotypic cellular changes and increased the activity of G6PDH. DDPM did not significantly influence the number of focal lesions but seemed to effect a decrease in phenotypic alteration within foci. The results suggest that changes in the nature of enzyme-altered foci may be correlated with enhancement or inhibition of tumorigenesis.

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