One of the underlying mechanisms of tumor promotion both in the skin and liver involves free radical mediated injury to informational macromolecules of target cells. A choline-deficient (CD) diet, which is an efficient liver tumor promoter, induces peroxidative damage of liver cell membrane lipids. By modifying components of a CD diet, we have shown that the efficacy of the promotion is correlated with the extent of lipid peroxidation. The substitution of fats in a CD diet with predominantly polyunsaturated fat and the addition of methapyrilene to a CD diet enhances membrane lipid peroxidation and the promoting effects. An antioxidant (BHT) and hypolipidemic peroxisome proliferators (BR.931 and DEHP) suppress both of these effects. Contrary to these findings, phenobarbital did not induce membrane lipid peroxidation, and its addition to a CD diet inhibited the diet-induced lipid peroxidation, though such a combination exerted a stronger promoting action. Thus, a CD diet and phenobarbital exert their promoting actions through different mechanisms. The consequence of membrane lipid peroxidation in the liver cells induced by a CD diet may be multiple. Our recent study of surface membrane insulin receptors of liver cells of rats fed a CD diet showed a decrease in number and an enhanced binding affinity leading to altered responsiveness of liver cells to insulin mediated glycogen synthesis. It is suggested that CD diet-induced lipid peroxidation leads to functional alterations of membrane receptors involved in cell growth control and may thereby exert its promoting action.
References
1.
1. Abanobi SE, Lombardi B, and Shinozuka H (1982). Stimulation of DNA synthesis and cell proliferation in the liver of rats fed a choline-devoid diet and their suppression by phenobarbital. Cancer Res.42:412–415.
2.
2. Birnboim HC (1982). Factors which affect DNA strand breakage in human leukocytes exposed to a tumor promoter, phorbal myristate acetate. Can. J. Physiol. Pharm.60:1359–1366.
3.
3. DeAngelo AB and Garrett CT (1983). Inhibition of development of preneoplastic lesions in the livers of rats fed a weakly carcinogenic environmental contaminant. Cancer Lett.20:199–205.
4.
4. Driedger PE and Blumberg PM (1980). Specific binding of phorbol ester tumor promoters. Proc. Nat. Acad. Sci.77:567–571.
5.
5. Emerit I and Cerutti PA (1982). Tumor promoter phorbol 12-myristate 13-acetate induces a clastogenic factor in human lymphocytes. Proc. Nat. Acad. Sci.79:7509–7513.
6.
6. Farber E (1984). The multistep nature of cancer development. Cancer Res.44:4217–4223.
7.
7. Freychet P (1976). Insulin receptor binding in hepatocytes. In: Methods in Receptor Research, Part 2, M Blecher (ed). Marcel Dekker, New York, pp. 385–428.
8.
8. Fusenig N and Dzarlieva R (1982). Phenotypic and chromosomal alterations in cell cultures as indicators of tumor-promoting activity. In: Carcinogenesis and Biological Effects of Tumor Promoters, E Heckes, N Fusenig, W Kunz, F Marks, and H Thielmann (eds). Raven, New York, pp. 201–216.
9.
9. Ghoshal AK and Farber E (1984). Induction of liver cancer by a dietary deficiency of choline and methionine without added carcinogens. Carcinogenesis5:1367–1370.
10.
10. Goldstein BD, Witz G, Amoruso M, Stone DS, and Troll W (1981). Stimulation of human polymorphonuclear leukocyte superoxide anion radical production by tumor promoters. Cancer Lett.11:257–262.
11.
11. Goodman DG, Ward JM, Squire RA, Chu KC, and Linhart MS (1978). Neoplastic and nonneoplastic lesions in aging F344 rats. Toxicol. App. Pharmacol.48:237–248.
12.
12. Hahn HKJ, Tuma DJ, Barak AJ, and Sorrell MF (1976). Effect of phenobarbital on lipid peroxidation in the liver. Biochem. Pharmacol.25:769–772.
13.
13. Hassis W and Abraham S (1957). Determination of glycogen and starch. In: Methods in Enzymology, Vol. III, S P Colowick and N Kaplan (eds). Academic Press, New York, pp. 34–38.
14.
14. Horvath PM and Ip C (1983). Synergistic effect of Vitamin E and selenium in the chemoprevention of mammary carcinogenesis in rats. Cancer Res.43:5335–5341.
15.
15. Kensler TW and Trush MA (1981). Inhibition of phorbol ester stimulated chemiluminescence in human polymorphonuclear leukocytes by retinoic acid and 5, 6- epoxyretinoic acid. Cancer Res.41:216–222.
16.
16. King MM and McCay PB (1983). Modulation of tumor incidence and possible mechanisms of inhibition of mammary carcinogenesis by dietary antioxidants. Cancer Res.43:2485–2490.
17.
17. Lijnsky W, Reuber MD, and Blackwell BN (1980). Liver tumors induced in rats by oral administration of the antihistaminic methapyrilene hydrochloride. Science209:817–819.
18.
18. Luetteke NC and Michalopoulos GK (1985). Partial purification and characterization of hepatocyte growth factor produced by rat hepatocellular carcinoma cells. Cancer Res.45:6331–6337.
19.
19. Ogawa K, Onoe T, and Takeuchi M (1981). Spontaneous occurrence of γ-glutamyl transpeptidase-positive hepatocytic foci in 105 week old Wistar and 72 week old Fischer 344 male rats. J. Nat. Cancer Inst.67:407–412.
20.
20. Peraino C, Fry RJM, and Staffeldt E (1971). Reduction and enhancement by phenobarbital of hepatocarcinogenesis induced in the rat by 2-acetyl-amino-fluorene. Cancer Res.31:1506–1512.
21.
21. Perera MIR, Demetris AJ, Katyal SL, and Shinozuka H (1985). Lipid peroxidation of liver microsome membranes induced by choline-deficient diets and its relationship to the diet-induced promotion of the induction of γ-glutamyltranspeptidase-positive foci. Cancer Res.45:2533–2538.
22.
22. Pitot HC and Sirica AE (1980). The stages of initiation and promotion in hepatocarcinogenesis. Biochim. Biophys. Acta605:191–215.
23.
23. Popp JA, Garvey LK, Hamnz TE Jr, and Swenberg JA (1985). Lack of hepatic promotional activity by the peroxisomal proliferating hepatocarcinogen di(2-ethylhexyl)phthalate. Carcinogenesis6:141–244.
24.
24. Popp JA, Scortichini BH, and Garvey LK (1985). Quantitative evaluation of hepatic foci of cellular alteration occurring spontaneously in Fischer 344 rats. Fund. Appl. Toxicology5:314–319.
25.
25. Rao MS, Lavwani ND, Watanabe TK, and Reddy JK (1984). Inhibitory effect of antioxidants ethoxyquin and 2-(3)-tert-butyl-4-hydroxyanisole on hepatic tumorigenesis in rats fed ciprofibrate, a peroxisome proliferator. Cancer Res.44:1072–1076.
26.
26. Reddy JK, Azarnoff DL, and Hignite CD (1980). Hypolipidemic hepatic peroxisome proliferators form a novel class of chemical carcinogens. Nature283:397–398.
27.
27. Reddy JK, Lalwani ND, Reddy MK, and Qureshi SA (1982). Excessive accumulation of autofluorescent Iipofuscin in the liver during hepatocarcinogenesis by peroxisome proliferators. Cancer Res.42:259–266.
28.
28. Rossi L, Ravera M, Repetti G, and Santi L (1977). Long-term administration of DDT or phenobarbital-Na in Wistar rats. Int. J. Cancer19:179–185.
29.
29. Rushmore TH, Ghoshal AK, and Farber E (1985). In vivo DNA damage in rat liver by a diet deficient in choline and methionine. Proc. Am. Assoc. Cancer Res.26: 99.
30.
30. Schulte-Hermann R and Parzefall W (1981). Failure to discriminate initiation from promotion of liver tumors in a long-term study with phenobarbital type inducer hexacholorocyclohexane and role of sustained stimulation of hepatic growth and monoxygenases. Cancer Res.41:4140–4146.
31.
31. Seglen PO (1976). Preparation of isolated rat liver cells. In: Methods in Cell Biology, Vol. XIII, DM Prescott. Academic Press, New York, pp. 29–83.
32.
32. Sells MA, Katyal SL, Sell S, Shinozuka H, and Lombardi B (1979). Induction of foci of altered γ-glutamyltranspeptidase-positive hepatocytes in carcinogen treated rats fed a diet devoid of choline. Br. J. Cancer40:274–283.
33.
33. Shinozuka H, Abanobi SE, and Lombardi B (1983). Modulation of tumor promotion in liver carcinogenesis. Emir. Health Persp.50:163–168.
34.
34. Shinozuka H, Demetris AJ, Katyal SL, and Perera MIR (1985). Interactions of barbiturates and choline-deficient diet in the promotion of liver carcinogenesis. In: Effects of Nutrition on Xenobiotic Metabolism, Am. Chem. Soc. Symposium Series 277: 327–336.
35.
35. Shinozuka H, Katyal SL, and Perera MIR (1985). Early detection of lipid peroxidation in the livers of rats fed methapyrilene. Fed. Proc.44: 1492.
36.
36. Shinozuka H and Lombardi B (1980). Synergistic effect of a choline-devoid diet and phenobarbital in promoting the emergence of foci of γ-glutamyltranspeptidase positive hepatocytes in the liver of carcinogen-treated rats. Cancer Res.40:3846–3849.
37.
37. Shinozuka H, Lombardi B, and Abanobi SE (1982). A comparative study of the efficacy of four barbiturates as promoters of the development of γ-glutamyltranspeptidase-positive foci in the liver of carcinogen treated rats. Carcinogenesis3:1017–1020.
38.
38. Slaga TJ, Kein-Szanto, AJP, Triplett LL, Yotti LP, and Trosko JE (1981). Skin tumor promoting activity of benzoyl peroxide, a widely used free radical generating compound. Science213:1023–1025.
39.
39. Solanki V, Rana RS, and Slaga TJ (1981). Diminution of mouse epidermal superoxide dismutase and catalase activities by tumor promoters. Carcinogenesis2:1141–1146.
40.
40. Staubli W, Bentley P, Bieri F, Frehlich 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.
41.
41. Takahashi S, Lombardi B, and Shinozuka H (1982). Progression of carcinogen induced foci of γ-glutamyltranspeptidase hepatocytes to hepatomas in rats fed a choline-deficient diet. Int. J. Cancer29:445–450.
42.
42. Ugazio G, Gabriel L, and Bardinor E (1967). Osservazioni sperimentale sui lipidi accumulati nil fegato di ratto alimentato con dieta colina priva. Lo Sperimentale117:1–17.
43.
43. Ward JM (1981). Morphology of foci of altered hepatocytes and naturally occurring hepatocellular tumors in F344 rats. Virchow. Arch. Path. Anal.390:339–345.
44.
44. Weddle CC, Hornbrook KK, and McCay PB (1976). Lipid peroxidation and alteration of membrane lipids in isolated hepatocytes exposed to carbon tetrachloride. J. Biol. Chem.251:4973–4978.
45.
45. Wilson RB, Kula NS, Newberne PM, and Conner MW (1973). Vascular damage and lipid peroxidation in choline deficient rats. Exp. Mol. Path.18:357–368.
46.
46. Witz G, Goldstein BD, Amoruso M, Stone DS, and Troll W (1980). Retinoid inhibition of superoxide anion radical production by human polymorphonuclear leukocytes stimulated with tumor promoters. Biochem. Biophys. Res. Comm.97:883–888.
47.
47. Yokoyama S, Sells MA, Reddy TV, and Lombardi B (1985). Hepatocarcinogenic and promoting action of a choline-devoid diet in the rat. Cancer Res.45:2834–2842.
