PERTURBATION OF RODENT HEPATOCYTE GROWTH-CONTROL BY NONGENOTOXIC HEPATOCARCINOGENS - MECHANISMS AND LACK OF RELEVANCE FOR HUMAN HEALTH (REVIEW)

During the development of new industrial and pharmaceutical chemicals, it is necessary to determine whether they are potential carcinogens. However, there are no shortterm tests available for nongenotoxic carci nogens that do not damage DNA yet cause tumours in rodent bioassays. T he peroxisome proliferators (PPs) constitute a diverse class of nongen otoxic carcinogens that include chemicals of therapeutic, industrial a nd environmental importance such as hypolipidaemic fibrate drugs, clin gwrap/medical tubing plasticizers and certain pesticides and solvents. PPs induce DNA synthesis and suppress apoptosis in rat and mouse hepa tocytes, leading to tumour formation. In addition to altering hepatocy te growth and survival, PPs cause peroxisome proliferation and the ind uction of enzymes of the beta-oxidation pathway. PPs mediate their bio logical responses in rodents via activation of the nuclear hormone rec eptor PPAR alpha (peroxisome proliferator activated receptor alpha) wh ich regulates expression of the genes associated with response to PPs. The mechanisms through which normally quiescent hepatocytes are recru ited into the cell cycle currently remain obscure. However, it is prob able that expression of hepatic cytokines by hepatic macrophages (Kupf fer cells) may be involved. In common with other classes of nongenotox ic carcinogen, there are remarkable species differences in response to PPs; humans respond to the fibrate hypolipidaemic PPs via a reduction in serum cholesterol but appear refractory to the adverse effects of PPs such as hepatic peroxisome proliferation, DNA synthesis and tumour formation. The molecular basis of the observed species differences in response to PPs is unclear at present, but recent data support a quan titative hypothesis wherein PPAR alpha expression levels are sufficien t in humans to mediate hypolipidaemia, but too low for transcriptional regulation of the full battery of genes associated with the adverse e ffects seen in rodents such as peroxisome proliferation, liver enlarge ment and tumours. A more detailed understanding of the mechanisms thro ugh which these chemicals cause tumours in rodents and how humans may differ will assist in extrapolation of rodent data to human risk asses sment.