Stimulation de la croissance hépatocytaire par les proliférateurs de peroxysomes.

Abstract

Les proliferateurs de peroxysomes, utilises en medecine comme medicaments hypolipemiants, sont des composes chimiques induisant des hepatocarcinomes chez les rongeurs sans provoquer de lesions de l' ADN. Cependant, ils n' induisent pas de tumeurs du foie chez l' homme. Chez les - rongeurs, les proliferateurs de peroxysomes induisent la replication de l' ADN des hepatocytes et inhibent la mort cellulaire par apoptose. Les proliferateurs de peroxysomes activent le recepteur nucleaire PPAR<alpha> (peroxisome prolifera-tor activated receptor <alpha>) qui controle l' expression des genes des enzymes de la voie de <beta>-oxydation des acides gras. Le TNF<alpha> (tumour necrosis factor <alpha>) semble necessaire a l' action des proliferateurs de peroxysomes mais les genes controlant la croissance hepatocytaire et regles par PPAR<alpha> n' ont pas ete identifies. La comprehension des mecanismes moleculaires induisant la proliferation hepatocytaire chez les rongeurs devrait permettre de mieux evaluer les risques que representent les proliferateurs de peroxysomes pour l' homme.

The majority of hepatocytes are normally quiescent in the adult liver, but can undergo rapid proliferation in response to nongenotoxic carcinogens. Nongenotoxic rodent hepatocarcinogens constitute a diverse group of chemicals of therapeutic, industrial and environmental significance. The peroxisome proliferator class of nongenotoxic carcinogens causes peroxisome proliferation and liver tumours in rats and mice, accompanied by liver enlargement and elevated transcription of cytochrome P4504A and acyl-CoA oxidase, a key enzyme in beta-oxidation of fatty acids. This diverse family of chemicals includes fibrate hypolipidaemic drugs, plasticizers solvents and agrochemicals. Peroxisome proliferators cause tumourigenesis in rodent liver by perturbing growth regulation, leading to the induction of DNA replication and hepatocyte proliferation. However, humans appear to be refractory to such adverse effects of peroxisome proliferators. The effects of peroxisome proliferators are mediated by the nuclear receptor PPARalpha (peroxisome proliferator activated receptor a) and the PPARalpha null mouse is refractory to the effects of peroxisome proliferators. PPARalpha heterodimerises with the retinoid X receptor (RXR) and binds to DNA at peroxisome proliferator response elements (PPREs) in the promotor regions of peroxisome proliferators-responsive genes such as rat acyl-CoA oxidase. The human acyl-CoA oxidase PPRE is inactive, possibly explaining the lack of peroxisome proliferation and acyl-CoA oxidase induction in humans. There is compelling evidence that tumour necrosis a (TNFalpha), which acts as a primer to sensitize hepatocytes to the proliferative effects of growth factors, is necessary for peroxisome proliferators to induce hepatocytes to enter S phase in rodents. Moreover, the peroxisome proliferator-induced S phase response in hepatocytes is not associated with gross dysregulation of cell cycle regulators such as the cyclin-dependent kinases or cyclin. Since humans are exposed to peroxisome proliferators therapeutically and in the environment, there is a need to elucidate the mechanisms through which non-genotoxic carcinogens cause cell proliferation and tumours in rodents, and how humans may differ, in order to determine whether any health risk exists. [References: 52]