The Use of Enzyme-Altered Foci for Risk Assessment of Hepatocarcinogens

Abstract

Chemically-induced hepatocarcinogenesis is characterized by the sequential appearance of phenotypically altered cell populations which can be identified by changes in the expression of a variety of markers such as canalicular adenosine triphosphatase (ATPase), γ-glutamyl transpeptidase, glucose-6-phosphatase and others (for review see Peraino et al., 1983). There is increasing evidence to suggest that at least some of these early enzyme-altered foci are precursor lesions which are causally related to the malignant transformation. This is substantiated by the sequential appearance of enzyme-altered foci and liver tumors and by the observation that neoplastic nodules and hepatocellular carcinoma show enzyme-patterns similar to those seen in preneoplastic foci (Fried- rich-Freksa et al., 1969; Goldfarb and Pugh, 1981; Bannasch et al., 1986). Moreover, strong quantitative relationships between the total volume of enzyme-altered tissue in liver and the subsequent development of liver tumors have been established (Emmelot and Scherer, 1980; Kunz et al., 1983, 1985). Enzyme-altered foci are monoclonal in origin (Rabes et al., 1982; Williams et al., 1983) and show a growth advantage over the surrounding normal hepatocytes (Rabes et al., 1979). The analysis of multiple marker enzymes within individual foci points towards a marked heterogeneity of phenotypes which is also reflected by differences in the proliferation rates of the foci (Buchmann et al., 1987; Peraino et al., 1984). The analysis of number and size of enzyme altered foci in liver can yield quantitative data on the effects of hepatocarcinogens at low, relevant dose levels. Moreover, these data inherit information on mechanistic aspects of carcinogenesis which may be of importance for the improvement of risk assessment of carcinogens and tumor promoting agents in liver.