[Cytochromes P450 and formation of reactive metabolites. Role in hepatotoxicity of drugs].
During the millennia of evolution, animals have been subjected to a relentless biological warfare mounted by the plants that they ingested. By duplication of an ancestral gene, divergent evolution of these 2 genes, and so forth, surviving animals have been endowed with multiple cytochromes P450s which can metabolize (and thus eliminate) a multitude of environmental liposoluble xenobiotics. A disadvantage of this system (fortunately limited by the concomitant installation of several protective systems) is that cytochrome P450 transforms some of these xenobiotics into chemically reactive metabolites. These free radicals or electrophilic metabolites attack tissue constituents, and may lead to mutation, cancer or tissue necrosis. Tissue necrosis affect mainly the liver, whose content in cytochrome P450 is particularly high. Indeed, reactive metabolites are usually extremely unstable, and react mainly in situ, in the same organ that forms them. When the formation of reactive metabolites is extensive, protective mechanisms are overwhelmed, extensive alterations of diverse hepatic constituents occur, and toxic hepatitis ensues. When the formation of reactive metabolites is moderate, severe toxic lesions do not occur. However, the covalent binding of reactive metabolites to hepatic proteins modifies the self of the subject. In some subjects, the presence of this modified self triggers immunization, and leads to immunoallergic hepatitis. The immune response may be directed either against protein (or peptide) epitopes modified by the presence of a reactive metabolite (reaction against modified self) and/or against normal, unmodified, epitopes of proteins (autoimmune reaction against the self, triggered by the modified self). Both metabolic factors, and the HLA phenotype, appear to modulate the likelihood of immunization.
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INSERM U-24, Hôpital Beaujon, Clichy.
D001327:Autoimmune Diseases / Q000235:genetics / Q000276:immunology; D056486:Chemical and Drug Induced Liver Injury / Q000209:etiology / Q000378:metabolism*; D065607:Cytochrome P-450 Enzyme Inhibitors; D003577:Cytochrome P-450 Enzyme System / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D006505:Hepatitis / Q000235:genetics / Q000276:immunology
D065607:Cytochrome P-450 Enzyme Inhibitors; D003577:Cytochrome P-450 Enzyme System
Cytochromes P450 et formation de métabolites réactifs. Rôle dans l'hépatotoxicité des médicaments.