Comparative Effects of Carcinogens on the Induction of Placental Glutathione S -Transferase-positive Liver Nodules in a Short-term Assay and of Hepatocellular Carcinomas in a Long-term Assay
Free accessResearch articleFirst published online June, 1985
Comparative Effects of Carcinogens on the Induction of Placental Glutathione S -Transferase-positive Liver Nodules in a Short-term Assay and of Hepatocellular Carcinomas in a Long-term Assay
The dose-dependent effects of three hepatocarcinogens were investigated by measuring the number and area of glutathione S-transferase placental form (GST-P)-positive foci and nodules appearing in the liver under short-term conditions (Experiment I) and evaluating the incidence of hepatocellular carcinoma after long-term chronic administration (Experiment II). For these purposes, three different doses of 2-acetylaminofluorene (2-AAF), 3'-methyl-4-dimethylaminoazobenzene (3'-Me-DAB), and DL-ethionine (ethionine) were given to male F344 rats for 6 weeks after a single injection of diethylnitrosamine (DENA) in Experiment I or for 104 weeks without initiation by DENA in Experiment II. In Experiment I, the induction of GST-P-positive foci and nodules by 2-AAF and 3'-Me-DAB was clearly dose-dependent. In contrast, ethionine showed enhancing effects inducing GST-P-positive foci and nodules only in groups given the highest dose level. Similarly, in Experiment II, induction of hepatocellular carcinomas by 2-AAF and 3'-Me-DAB was clearly dose-dependent, whereas liver neoplasms were only induced by the highest dose level of ethionine. These results indicate that degree of induction of GST-P positive foci and nodules in a short-term in vivo test for liver carcinogens corresponds with the incidences of hepatocellular carcinomas revealed in a long-term in vivo assay.
References
1.
1. Ames RN, McCann I, and Yamazaki E (1975). Methods for detecting carcinogens and mutagens with the Salmonella/mammalian-microsome mutagenicity test. Mutat. Res.31:347–364.
2.
2. Deml E and Oesterle D (1980). Histochemical demonstration of enhanced glutathione content in enzyme-altered islands induced by carcinogens in rat liver. Cancer Res.40:490–491.
3.
3. Eriksson LC, Astrom A, Depierre JW, and Bock KW (1981). Induction of drug-metabolizing enzymes in preneoplastic liver nodules. Biochem. Soc. Trans.9: 271.
4.
4. Farber E and Ichinose H (1958). The prevention of ethionine-induced carcinoma of the liver in rats by methionine. Cancer Res.18:1209–1213.
5.
5. Fiala S, Fiala AE, and Dixton D (1972). γ-Glutamyltranspeptidase in transplantable chemically induced rat hepatomas and “spontaneous” mouse hepatomas. J. Natl. Cancer Inst.48:1393–1401.
6.
6. Fischer G, Ullrich D, Katz N, Bock KW, and Schauer A (1983). Immunohistochemical and biochemical detection of uridine diphosphate-glucuronyltransferase (UDP-GT) activity in putative preneoplastic liver foci. Virchous Arch. (Cell Pathol.)42:193–200.
7.
7. Goldfarb S (1973). Morphological and histochemical study of carcinogenesis of the liver in rats fed 3′-methyl-4-dimethylaminobenzene. Cancer Res.33:1119–1128.
8.
8. Graham RC Jr and Karnofsky MJ (1966). The early stage of absorption of injected horseradish peroxidase in the proximal convoluted tubules of mouse kidney: ultrastructural cytochemistry by a now technique. J. Histochem. Cytochem.14:291–302.
9.
9. Hacker HJ, Moore MA, Mayer D, and Bannasch P (1982). Correlative histochemistry of some enzymes of carbohydrate metabolism in preneoplastic and neoplastic lesions in the rat liver. Carcinogenesis3:1265–1272.
10.
10. Herren SL, Pereira MA, Britt AL, and Khoury MK (1982). Initiation/promotion assay for chemical carcinogens in rat liver. Toxicol. Lett.12:143–150.
11.
11. Hsu S-M, Raine L, and Fanger H (1981). Use of avidin-biotin-peroxidase complex (ABC) in immunoperoxidase techniques: A comparison between ABC and unlabeled antibody (PAP) procedures. J. Histochem. Cytochem.29:577–580.
12.
12. Ito N, Tatematsu M, Nakanishi K, Hasegawa R, Takano T, Imaida K, and Ogiso T (1980). The effects of various chemicals on the development of hyperplastic liver nodules in hepatectomized rats treated with N-nitrosodiethylamine or N-2-fluorenylacetamide. Gann71:832–842.
13.
13. Ito N, Tsuda H, Hasegawa R, and Imaida K (1982). Sequential observation of pathomorphologic alterations in preneoplastic lesions during the promoting stage of hepatocarcinogenesis and the development of short-term test system for hepatopromoters and hepatocarcinogens. Toxicol. Pathol.10:37–49.
14.
14. Ito N, Tsuda H, Hasegawa R, and Imaida K (1983). Comparison of the promoting effects of various agents in induction of preneoplastic lesions in rat liver. Environ. Health Perspect.50:131–138.
15.
15. Ito N, Shirai T, Fukushima S, and Hirose M (1984). Dose-response study of urinary bladder carcinogenesis in rats by N-butyl-N-(4-hydroxybutyl)nitrosamine. J. Cancer Res. Clin. Oncol.108:169–173.
16.
16. Ito N, Ogiso T, Fukushima S, Shibata M, and Hagiwara A (1984). Carcinogenicity of captafol in B6C3F1 mice. Gann75:853–865.
17.
17. Kunz W, Schaude G, Schwarz M, and Tennekes H (1982). Quantitative aspects of drug-mediated tumor promotion in liver and its toxicological implications. In: Carcinogenesis—A Comprehensive Survey: Cocarcinogenesis and Biological Effects of Tumor Promoters, E Hecker, NE Fusenig, W Kunz, F Marks, and HW Thielmann (eds). Raven Press, New York, Vol. 7, pp. 111–125.
18.
18. Levin W, Lee AYH, Thomas PE, Ryan D, Kizer K, and Griffin MJ (1978). Identification of epoxide hydrase as the preneoplastic antigen in rat liver hyperplastic nodules. Proc. Natl. Acad. Sci. USA75:3240–3243.
19.
19. Lin J-C, Kligman L, and Farber E (1980). Purification and partial characterization of a preneoplastic antigen in liver carcinogenesis. Cancer Res.40:3755–3762.
20.
20. Lindahl R, Evces S, and Sheng W-L (1982). Expression of the tumor aldehyde dehydrogenase phenotype during 2-acetylaminofluorene-induced rat hepatocarcinogenesis. Cancer Res.42:577–582.
21.
21. More M, Kaku T, Dempo K, Satoh M, Kaneko A, and Onoe T (1980). Histochemical investigation of precancerous lesions induced by 3′-methyl-4-dimethylaminoazobenzene. Gann: Monograph Cancer Res.35:103–114.
22.
22. Ogawa K, Solt DB, and Farber E (1980). Phenotypic diversity as an early property of putative preneo-plastic hepatocytes in liver carcinogenesis. Cancer Res.40:725–733.
23.
23. Pienta RJ, Poiley, JA, and Lebherz WB III (1977). Morphological transformation of early passage golden Syrian hamster embryo cells derived from cryopreserved primary cultures as a reliable in vitro bioassay for identifying diverse carcinogens. Int. J. Cancer19:642–655.
24.
24. Preussmann R (1980). The problem of thresholds in chemical carcinogenesis: some views on theoretical and practical aspects. J. Cancer Res. Clin. Oncol.97:1–14.
25.
25. Rinks SJ and Legator MS (1979). Chemical characterization of 465 known or suspected carcinogens and their correlation with mutagenic activity in the Salmonella typhimurium system. Cancer Res.39:3289–3318.
26.
26. Sato K, Kitahara A, Satoh K, Ishikawa T, Tatematsu M, and Ito N (1984). The placental form of glutathione S-transferase as a new marker protein for preneoplasia in rat chemical hepatocarcinogenesis. Gann75:199–202.
27.
27. Sawada N and Tsukada H (1983). Elevation of γ-glutamyltranspeptidase activity in rat liver induced by feeding of butylated hydroxytoluene. Gann74:806–809.
28.
28. Schor N, Ogawa K, Lee G, and Farber E (1978). The use of DT-diaphorase for the detection of foci of early neoplastic transformation in rat liver. Cancer Lett.5:167–171.
29.
29. Stäubli W, Bentley P, Bieri F, Fröhlich E, and Waechter F (1984). Inhibitory effect of nafenopin upon the development of diethylnitrosamine-induced enzyme-altered foci within the rat liver. Carcinogenesis5:41–46.
30.
30. Sugimura T, Sato S, Nagao M, Yahagi T, Matsushima T, Seino Y, Takeuchi M, and Kawachi T (1976). Overlapping of carcinogens and mutagens. In: Fundamentals in Cancer Prevention, P Magee, N Takayama, S Sugimura, and T Matsushima (eds). University Park Press, Baltimore, pp. 191–215.
31.
31. Takano T, Tatematsu M, Hasegawa R, Imaida K, and Ito N (1980). Dose-response relationship for the promoting effect of phenobarbital on the induction of liver hyperplastic nodules in rats exposed to 2-fluorenylacetamide and carbon tetrachloride. Gann71:580–581.
32.
32. Tamano S, Tsuda H, Fukushima S, Masui T, Hosoda K, and Ito N (1983). Dose- and sex-dependent effects of 2-acetylaminofluorene, 3′-methyl-4-dimethylaminoazobenzene, and DL-ethionine in induction of γ-glutamyltranspeptidase-positive liver cell foci in rats. Cancer Lett.20:313–321.
33.
33. Tatematsu M, Hasegawa R, Imaida K, Tsuda H, and Ito N (1983). Survey of various chemicals for initiating and promoting activities in a short-term in vivo system based on generation of hyperplastic liver nodules in rats. Carcinogenesis4:381–386.
34.
34. Tatematsu M, Kaku T, Medline A, Erikson L, Roomi W, Sharma RN, Murray RK, and Farber E (1983). Markers of liver neoplasia—Real or fictional?. In: Application of Biological Markers to Carcinogen Testing, HA Milman and S Sell (eds). Plenum Publishing Co., New York, pp. 25–42.
35.
35. Tatematsu M, Mera Y, Ito N, Satoh K, and Sato K (1985). Relative merits of immunohistochemical demonstrations of placental, A, B, and C forms of glutathione S-transferase and histochemical demonstration of γ-glutamyltransferase as markers of altered foci during liver carcinogenesis in rats. Carcinogenesis, in press.
36.
36. Tatematsu M, Nakanishi K, Murasaki G, Miyata Y, Hirose M, and Ito N (1979). Enhancing effect of inducers of liver microsomal enzymes on induction of hyperplastic liver nodules by N-2-fluorenyl-acetamide in rats. J. Natl. Cancer Inst.63:1411–1416.
37.
37. Tatematsu M, Shirai T, Tsuda H, Miyata Y, Shinohara Y, and Ito N (1977). Rapid production of hyperplastic liver nodules in rats treated with carcinogenic chemicals: a new approach for an in vivo short-term screening test for hepatocarcinogens. Gann68:499–507.
38.
38. Tsuda H, Hagiwara A, Shibata M, Ohshima M, and Ito N (1982). Carcinogenic effect of carbazole in the liver of (C57BL/6N × C3H/Hen)F1 mice. J. Natl. Cancer Inst.69:1383–1389.
39.
39. Tsuda H, Hasegawa R, Imaida K, Masui T, Moore MA, and Ito N (1984). Modifying potential of thirty-one chemicals on the short-term development of γ-glutamyltranspeptidase-positive foci in diethylnitrosamine-initiated rat liver. Gann75:876–883.
40.
40. Tsuda H, Lee G, and Farber E (1980). Induction of resistant hepatocytes as a new principle for a possible short-term in vivo test for carcinogens. Cancer Res.40:1157–1164.
