title: Inactivation of stress protein p8 increases murine carbon tetrachloride hepatotoxicity via preserved CYP2E1 activity.
abstract: The p8 protein is a transcription factor that regulates the expression of genes involved in cell defense against the adverse effects of stress. Its expression is strongly, rapidly, and transiently induced in most cells on exposure to various stress agents. This study assessed the role of p8 in the response of the liver to CCl(4)-induced injury. We found that p8 was indeed overexpressed in the liver after CCl(4) administration. Hepatic injury following CCl(4) injection was monitored in wild-type and p8(-/-) mice. Serum alanine and aspartate aminotransferase activities were higher and peaked earlier in p8(-/-) mice than in wild-type mice, which is in agreement with the observation of significantly larger areas of necrosis in p8(-/-) liver. Absence of p8 expression is therefore associated with increased liver sensitivity to CCl(4). In fact, CCl(4) toxicity is mediated by derivatives generated by its conversion by the enzyme CYP2E1. It is known that CYP2E1 is downregulated in the liver during the first hours following CCl(4) administration as part of a self-defense mechanism. We found that CYP2E1 downregulation was significantly delayed in p8(-/-) liver compared with wild-type liver, allowing increased production of toxic CCl(4) derivatives. In conclusion, inactivation of the p8 gene increases liver sensitivity to CCl(4), as it appears to delay the triggering of CYP2E1 downregulation. The p8 protein is therefore an important element of hepatocyte stress response.
authors.affiliation: INSERM Unité 624, Stress Cellulaire, Parc Scientifique et Technologique de Luminy, Marseille, France.
authors.forename: David
authors.initials: D
authors.lastname: Taïeb
authors.forename: Cédric
authors.initials: C
authors.lastname: Malicet
authors.forename: Stéphane
authors.initials: S
authors.lastname: Garcia
authors.forename: Palma
authors.initials: P
authors.lastname: Rocchi
authors.forename: Christiane
authors.initials: C
authors.lastname: Arnaud
authors.forename: Jean-Charles
authors.initials: JC
authors.lastname: Dagorn
authors.forename: Juan L
authors.initials: JL
authors.lastname: Iovanna
authors.forename: Sophie
authors.initials: S
authors.lastname: Vasseur
mesh_terms: D000818:Animals; D002251:Carbon Tetrachloride / Q000009:adverse effects*; D056486:Chemical and Drug Induced Liver Injury / Q000209:etiology / Q000235:genetics / Q000503:physiopathology*; D019392:Cytochrome P-450 CYP2E1 / Q000096:biosynthesis* / Q000235:genetics; D004268:DNA-Binding Proteins / Q000096:biosynthesis* / Q000235:genetics; D015536:Down-Regulation; D006360:Heat-Shock Proteins / Q000096:biosynthesis* / Q000235:genetics; D051379:Mice; D023421:Models, Animal; D009363:Neoplasm Proteins / Q000096:biosynthesis* / Q000235:genetics
chemical_list: D004268:DNA-Binding Proteins; D006360:Heat-Shock Proteins; D009363:Neoplasm Proteins; C491644:Nupr1 protein, mouse; D002251:Carbon Tetrachloride; D019392:Cytochrome P-450 CYP2E1