Peroxisome proliferators and receptor-mediated hepatic carcinogenesis.
The peroxisome proliferators represent an important group of hepatic carcinogens in rodents that act via the nuclear receptor PPARalpha. The primary role of PPARalpha in mediating this response had led to the further characterization of potential events downstream that likely enable the carcinogenic response, including increased peroxisomal fatty acid beta oxidation and the modulation of hepatocellular replication and death, either generally or in preneoplastic lesions. A cooperative role of Kupffer cell activation has been proposed to function in the modulation of hepatocellular proliferation in rodent liver by peroxisome proliferators, but data that confirm or refute this proposal are mixed. Presently there is no evidence that links the Kupffer cell activation by peroxisome proliferators directly to the development of liver tumors. There are marked species differences in susceptibility to peroxisomal proliferation, and active investigation concerning the molecular basis of these differences continues.
Cattley
Russell C
RC
Department of Pathology, Amgen Inc., Thousand Oaks, California 91320, USA. rcattley@amgen.com
D000818:Animals; D002273:Carcinogens / Q000633:toxicity*; D002455:Cell Division / Q000187:drug effects; D002471:Cell Transformation, Neoplastic; D005227:Fatty Acids / Q000378:metabolism; D006801:Humans; D007728:Kupffer Cells / Q000378:metabolism; D008099:Liver / Q000187:drug effects / Q000473:pathology; D008113:Liver Neoplasms / Q000139:chemically induced* / Q000201:enzymology / Q000378:metabolism; D020025:Peroxisome Proliferators / Q000633:toxicity*; D020675:Peroxisomes; D018160:Receptors, Cytoplasmic and Nuclear / Q000235:genetics / Q000502:physiology*; D013045:Species Specificity
D002273:Carcinogens; D005227:Fatty Acids; D020025:Peroxisome Proliferators; D018160:Receptors, Cytoplasmic and Nuclear