Inactivation of stress protein p8 increases murine carbon tetrachloride hepatotoxicity via preserved CYP2E1 activity.
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.
Taïeb
David
D
INSERM Unité 624, Stress Cellulaire, Parc Scientifique et Technologique de Luminy, Marseille, France.
Malicet
Cédric
C
Garcia
Stéphane
S
Rocchi
Palma
P
Arnaud
Christiane
C
Dagorn
Jean-Charles
JC
Iovanna
Juan L
JL
Vasseur
Sophie
S
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
D004268:DNA-Binding Proteins; D006360:Heat-Shock Proteins; D009363:Neoplasm Proteins; C491644:Nupr1 protein, mouse; D002251:Carbon Tetrachloride; D019392:Cytochrome P-450 CYP2E1