JSTOR is a not-for-profit service that helps scholars, researchers, and students discover, use, and build upon a wide range of content in a trusted digital archive. We use information technology and tools to increase productivity and facilitate new forms of scholarship. For more information about JSTOR, please contact support@jstor.org.. The National Institute of Environmental Health Sciences (NIEHS) and Brogan & Partners are collaborating with JSTOR to digitize, preserve and extend access to Environmental Health Perspectives. Specific biochemical changes occurring during hepatocarcinogenesis have been sought by many investigators. The development of multistage models for hepatocarcinogenesis in the rodent has renewed interest in such marker alterations in preneoplastic as well as neoplastic hepatocytes. Preneoplastic altered hepatic foci (AHF) exhibit specific histomorphologic changes as viewed with tinctorial stains and show a variety of biochemical changes as evidenced by enzyme and immunohistochemistry and by other histochemical markers. During the reversible stage of promotion when AHF are scored by multiple markers, the distribution of markers within these lesions differs with the use of different promoting agents. One interpretation of this finding is that each promoting agent stimulates the replication of a set of initiated cells exhibitingthe phenotypic characteristics of a specific programmed phenotype. The same markers score AHF during the stage of progression, but many AHF in this stage are phenotypically heterogeneous, exhibiting in tissue sections a "focus-in-focus" pattern of marker alteration. These latter changes can be correlated with the appearance of karyotypic alterations in preneoplastic hepatocytes. On the other hand, it has been difficult to demonstrate the activation, either mutational or transcriptional, of proto-oncogenes until this stage of progression in rat hepatocarcinogenesis. Thus, a study of biochemical and molecular markers during the stages of hepatocarcinogenesis may lead to a better understanding of potential mechanisms involved in the development of neoplasia through the stages of initiation, promotion, and progression.
The nonsteroidal antiestrogen tamoxifen increases the incidence of rat liver cancer through a variety of mechanisms. To compare the effects of tamoxifen (TAM) and a structurally similar analog toremifene (TOR) on rat liver, we determined the ploidy distribution for hepatocytes isolated from rats treated for 18 months with these antiestrogens or the estrogenic compound mestranol (MS). Female Sprague-Dawley rats were subjected to a 70% partial hepatectomy and administered the solvent, trioctanoin, or diethylnitrosamine (10 mg DEN/kg). After a 2-week recovery from the surgery, the rats were administered a basal diet or one containing TAM (250 or 500 ppm), TOR (250, 500, or 750 ppm), or MS (0.2 ppm) for 18 months. Pathologic changes in the liver were examined in the 15-22 rats per treatment group at the 18-month time point. An increased incidence of hepatocellular carcinomas (HCC) was detected in the 500 ppm TAM group, but not with the other treatments that did not include DEN. Both TOR and TAM promoted formation of DEN-initiated HCCs. At sacrifice, four to five rats per group were perfused and the hepatocytes isolated and cultured. Karyotypic analysis was performed on colcemid-blocked cells after 2 days in culture. The hepatic ploidy distribution was characterized in Giemsa-stained metaphase spreads. These studies indicated that chronic treatment with TAM alone resulted in a shift from tetraploid to diploid, as was also observed for rats treated once with DEN. TOR and MS alone did not cause this change in hepatic ploidy at the doses examined. A shift toward an increased content of diploid hepatocytes occurred in all rats treated once with DEN followed by TAM, TOR, or MS. These results indicate that tamoxifen administration results in a shift toward growth of diploid hepatocytes, thus contributing to its carcinogenic action in the rat liver.
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