Receptor-mediated hepatocarcinogenesis: role of hepatocyte proliferation and apoptosis.
The rodent liver is a target organ for the action of several non-genotoxic carcinogens. These include dioxins, polychlorinated biphenyls, phenobarbital, peroxisome proliferators and organochlorine pesticides. These chemicals disrupt the homeostasis of the liver by perturbing hepatocyte cell death and proliferation, causing hyperplasia leading to tumour formation. Significant progress has been made towards elucidating the mechanisms of action of these toxicants since the discovery of receptors that bind specific classes of xenobiotics. Dioxins and polychlorinated biphenyls bind to the aryl hydrocarbon receptor, phenobarbital binds to the constitutive androstane receptor and peroxisome proliferators act via the their activated receptor alpha. These three receptors have ligand-dependent transcription activities and therefore mediate changes in gene expression in response to toxicant exposure. The development of transgenic mouse strains where the genes for these receptors are disrupted has demonstrated that receptor activity is essential for the toxicity of these carcinogens. This implies that changes in the expression of key target genes control proliferation and apoptosis in the xenobiotic-induced hepatocyte phenotype.
Syngenta Central Toxicology Laboratory, Alderley Park, Macclesfield, Cheshire SK10 4TJ, UK. jason.oliver@syngenta.com
Jason D
JD
Oliver
Ruth A
RA
Roberts
D000818:Animals; D017209:Apoptosis; D002273:Carcinogens / Q000633:toxicity*; D002455:Cell Division / Q000187:drug effects; D004026:Dieldrin / Q000633:toxicity; D004147:Dioxins / Q000633:toxicity; D022781:Hepatocytes / Q000187:drug effects / Q000473:pathology; D008099:Liver / Q000187:drug effects* / Q000473:pathology; D008113:Liver Neoplasms / Q000139:chemically induced* / Q000473:pathology; D020025:Peroxisome Proliferators / Q000633:toxicity; D010634:Phenobarbital / Q000633:toxicity; D011078:Polychlorinated Biphenyls / Q000633:toxicity; D011725:Pyridines / Q000633:toxicity; D018160:Receptors, Cytoplasmic and Nuclear / Q000187:drug effects* / Q000235:genetics / Q000502:physiology; D012377:Rodentia
D002273:Carcinogens; D004147:Dioxins; D020025:Peroxisome Proliferators; D011725:Pyridines; D018160:Receptors, Cytoplasmic and Nuclear; C028474:1,4-bis(2-(3,5-dichloropyridyloxy))benzene; D011078:Polychlorinated Biphenyls; D004026:Dieldrin; D010634:Phenobarbital