The relevance of hepatic peroxisome proliferation in rats to assessment of human carcinogenic risk for pharmaceuticals.
There exists a strong association between the ability of drugs and other chemicals to induce hepatic peroxisomes in rodents and to increase the frequency of liver tumors in these same species. Despite several years of intensive investigation, a plausible mechanism causally relating peroxisome induction to tumor formation has not been found. Two major theories of how such compounds produce tumors--prolonged oxidative stress and cellular growth dysregulation--have limited experimental support. The oxidative stress demonstrated in rodents as a consequence of peroxisomal activity may be irrelevant to man since primates appear to be much less susceptible to peroxisome proliferation than are rats or mice. Cellular growth dysregulation and other effects of test materials that often accompany--but are not directly attributable to--peroxisome proliferation in rodents can be assessed in other, more relevant species if a causal relationship between their presence and tumor development is ultimately shown in rodents. Currently, there is no reason to specifically avoid the clinical assessment and commercial development of new therapeutic drugs that induce peroxisomes in rodents if other measurements indicate the absence of DNA damage or growth dysregulation at reasonable exposures in relevant species.
Pfizer Central Research Laboratories, Groton, Connecticut 06340.
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Kluwe
D000818:Animals; D015197:Carcinogenicity Tests; D002455:Cell Division; D004353:Drug Evaluation, Preclinical; D006801:Humans; D008099:Liver / Q000166:cytology / Q000648:ultrastructure*; D008113:Liver Neoplasms / Q000453:epidemiology / Q000209:etiology; D008830:Microbodies / Q000187:drug effects / Q000502:physiology*; D018384:Oxidative Stress; D051381:Rats; D018570:Risk Assessment