Hepatocarcinogenesis: How Do Peroxisome Proliferators Relate?

Abstract

There is an increasing awareness that many peroxisome proliferators are being introduced into our environment and many of these have shown carcinogenic activity in some rodent species. The agents involved include drugs (e.g., hypolipdemic agents of several chemical structures including HMG CoA reductase inhibitors) and industrial chemicals. The neoplasms seen are mainly in the liver with a variable incidence in the pancreas. The association between peroxisome proliferation and neoplasms is impressive. Yet, there are several seemingly fundamental differences between carcinogenic peroxisome proliferators and mutagenic or genotoxic chemical carcinogens. Peroxisome proliferators in general are neither mutagenic nor genotoxic and do not induce precancerous hepatic lesions and liver cell cancer until they have reached the late stage. With many agents, it appears that a considerable degree of peroxisome proliferation must take place for them to be carcinogenic. One poorly documented speculation is that peroxisome proliferators induce cancer by acting mainly as promoters, presupposing that the animals being tested are “preinitiated,” a conclusion that is scientifically indefensible. This presentation covers a comparison between the key requirements for cancer development with genotoxic agents and those seen with peroxisome proliferators, and discusses the methylation of genes for selective enzymes of the resistance phenotype induced by mutagenic carcinogens.

References

Barbason, H. , Rassenfosse, C. , and Betz, E.H. (1983). Promotion mechanism of phenobarbital and partial hepatectomy of DENA hepatocarcinogenesis cell kinetics effect. Br. J. Cancer 47:517–525.

Columbano, A. , Ledda-Columbano, G.M. , Ennas, M.G. , Curto, M. , Chelo, A. , and Pani, P. (1990). Cell proliferation and promotion of rat liver carcinogenesis: different effect of hepatic regeneration and mitogen induced hyperplasia in the development of enzyme-altered foci. Carcinogenesis 11:771–776.

De La Iglesia, F.A. and Farber, E. (1981) Hepatocarcinogenesis of hypolipidemic agents, in: Organ-Directed Toxicity-Chemical Indices and Mechanisms. S.S. Brown and D.S. Davies (eds.). Pergamen Press: Oxford, pp. 175–182.

Ecki, P.M. , Meyer, S.A. , Whitcomb, W.P. , and Jirtle, R.L. (1988). Phenobarbital reduces EGF receptors and the ability of physiological concentration of calcium to suppress hepatocyte proliferation. Carcinogenesis 9:479–483.

Farber, E. and Sarma, D.S.R. (1987). Biology of disease: Hepatocarcinogenesis: A dynamic cellular perspective. Lab Invest. 56:4–22.

Greaves, P. , Irisarri, E. , and Monro, A.M. (1986). Hepatic foci of cellular and enzymatic alteration and nodules in rats treated with clofibrate or diethylnitrosamine followed by phenobarbitol: their rate of onset and reversibility. J. Natl. Cancer Inst. 76:475–484.

Laconi, E. , Li, F. , Semple, E. , Rao, P.M. , Rajalakshmi, S. , and Sarma, D.S.R. (1988). Inhibition of DNA synthesis in primary cultures of hepatocytes by orotic acid. Carcinogenesis 9:675–677.

Lea, M.A. , Lueke, A. , Assad, S. , and Ayyala, S. (1990). Inhibitory effects of orotate on precursor incorporation into nucleic acids. Chem-Biol. Interact. 75:49–59.

Ledda-Columbano, G.M. , Columbano, A. , Ennas, M.G. , Coni, P. , Sarma, D.S.R. , and Pani, P. (1989). Further evidence that mitogen-induced cell proliferation does not support the formation of enzyme-altered islands in rat liver by carcinogens. Carcinogenesis 10:847–850.

10.

Pichiri-Coni, G. , Coni, P. , Laconi, E. , Schwarze, P.E. , Seglen, P.E. , Rao, P.M. , Rajalakshmi, S. , and Sarma, D.S.R. (1990). Studies on the mitoinhibitory effect of orotic acid on hepatocytes in primary culture. Carcinogenesis 11:981–984.

11.

Rao, M.S. and Reddy, J.K. (1987). Phenotypic Properties of Preneoplastic Hepatic Lesions Induced by Peroxisome Proliferators in Rats. H.D. Fahimi and H. Sies (eds.) Berlin: Springer-Verlag, pp. 263–272.

12.

Rao, M.S. , Lalwani, N.D. , and Reddy, J.K. (1984). Sequential histologic study of rat liver during peroxisome proliferator(4-chloro-6(2, 3-xylidino)-2-(pyrimidinylthio)-acetic acid)(WY-14, 643)-induced carcinogenesis. J. Natl. Cancer Inst. 73:983–990.

13.

Roomi, M.W. , Rao, M.S. , Reddy, J.K. , Cameron, R.G. , and Farber, E. (1987). Modulation of the phenotypic expression of rat hepatocyte nodules by a hypolipidemic agent, ciprofibrate. Proc. Am. Assoc. Cancer Res. 28:143.