NUMBER OF SIMULTANEOUSLY EXPRESSED ENZYME ALTERATIONS CORRELATES WITHPROGRESSION OF N-ETHYL-N-HYDROXYETHYLNITROSAMINE-INDUCED HEPATOCARCINOGENESIS IN RATS

Preneoplastic and neoplastic liver cell lesions, induced by EHEN (N-et hyl-N-hydroxyethylnitrosamine) in rats, were investigated to establish the numbers of simultaneously expressed altered enzyme phenotypes wit hin the lesion cells. The lesions were divided into 5 classes on the b asis of altered expression in one or more of the following 5 enzymes: glutathione S-transferase placental form, glucose-6-phosphate dehydrog enase, glucose-6-phosphatase, adenosine triphosphatase, and gamma-glut amyl transpeptidase. Class 1 lesions contained cells expressing one al tered enzyme. Similarly, class 2, 3, 4 and 5 lesions had cells simulta neously expressing 2, 3, 4, and 5 enzyme alterations, respectively. Fo ur histopathological categories of lesions, ACF (altered cell foci) (2 74 lesions), HN (hyperplastic nodules) (47 lesions), HCC (hepatocellul ar carcinomas) (99 lesions) and THC (transplanted hepatocellular carci nomas) (5 lesions) were studied. Proliferation potential was assessed in terms of 5-bromo-2'-deoxyuridine (BrdU) incorporation. The distribu tion profiles of classes 1 to 5 showed a clear reciprocal change from low class (I to 2 enzymes) predominance in ACF to high class (4 to 5 e nzymes) predominance in HN. Increase of BrdU labeling indices was clea rly correlated with progression from HN to HCC. Only a small populatio n of class 5 ACF showed a high BrdU labeling index, indicating particu lar potential for further development. Thus, the stages of EHEN-induce d neoplasia were found to be characterized by gradual increase in the number of altered enzyme phenotypes, with acquisition of proliferative potential being associated with further progression towards malignant conversion.