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Hepatocarcinogenesis: How Do Peroxisome Proliferators Relate?

Department of Pathology University of Toronto Medical Sciences Building Toronto, Ontario, Canada M55 1A8

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.

International Journal of Toxicology, Vol. 11, No. 3, 363-367 (1992)
DOI: 10.3109/10915819209141876


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