Xenobiotic-induced peroxisome proliferation: role of tissue specificity and species differences in response in the evaluation of the implications for human health.
Significant increases in the number of peroxisomes and in the activity of H2O2 generating peroxisomal fatty acid beta-oxidation enzyme system occur in liver parenchymal cells of mice, rats and certain other species exposed to several structurally dissimilar hypolipidemic drugs and certain phthalate-ester plasticizers. These agents, referred to as peroxisome proliferators, are considered as novel hepatocarcinogenic agents in view of their non-mutagenic and non-genotoxic nature. The lack of mutagenicity of these agents combined with consistent coupling of proliferation of H2O2 generating peroxisomes led to the hypothesis that persistent proliferation of peroxisomes serves as an endogenous initiator of neoplastic transformation by inducing oxidative stress. The mechanism by which oxidative stress leads to neoplastic transformation is, however, not clear. This postulated link between peroxisome proliferation and carcinogenicity implies that tumors should develop only in organs displaying profound peroxisome proliferation. Current evidence indicates that maximal peroxisome proliferation is a tissue-specific phenomenon, restricted largely to the hepatocyte. This tissue-specific biological response suggests that interaction of these structurally dissimilar xenobiotics with a receptor(s) might be the mechanism responsible for peroxisome proliferation and the selective increase in the rate of transcription of peroxisomal fatty acid beta-oxidation enzyme genes without significantly affecting the transcriptional rate of peroxisomal marker enzyme catalase gene. Identification and molecular characterization of peroxisome proliferator specific receptor(s) and elucidation of the mechanisms responsible for the differences in interspecies responses will be necessary for the evaluation of the implications for human health, since the carcinogenicity is not directly attributable to the chemical but to the adaptive responses of the host.
D000818:Animals; D004051:Diethylhexyl Phthalate / Q000633:toxicity; D006801:Humans; D000960:Hypolipidemic Agents / Q000633:toxicity; D008114:Liver Neoplasms, Experimental / Q000139:chemically induced* / Q000235:genetics / Q000473:pathology; D016031:Liver Transplantation; D051379:Mice; D008830:Microbodies / Q000201:enzymology / Q000473:pathology*; D051381:Rats; D013045:Species Specificity
D000960:Hypolipidemic Agents; D004051:Diethylhexyl Phthalate