Inhibition of Heme Oxygenase-1 Protects Against Tissue Injury in Carbon Tetrachloride Exposed Livers

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• 作者：Christian Eipel ; Michaela Eisold ; Harald Schuett ; Brigitte Vollmar
• 刊名：Journal of Surgical Research
• 出版年：2007
• 出版时间：1 May 2007
• 年：2007
• 卷：139
• 期：1
• 页码：113-120
• 全文大小：829 K

文摘

Background/Aims

During the metabolism of the hepatotoxin carbon tetrachloride (CCl₄) by cytochrome P450, heme, and free radicals are released. Heme oxygenase (HO-1) is an enzyme that is induced by heme as well as oxidative stress and has been reported to be involved in mediating protection against toxic liver injury. The purpose of the present study was to specify the role of HO-1 in CCl₄-hepatotoxicity.

Methods and Results

We could demonstrate an up-regulation of HO-1 protein in CCl₄-exposed liver tissue that reaches its maximum after 6 to 12 h, along with intrahepatic leukocyte accumulation and tissue injury. When animals were pretreated with hemin for augmentation of HO-1 expression, CCl₄-exposure was associated with a reduction of intrahepatic leukocyte accumulation, while inhibition of CCl₄-induced HO-1 expression by tin protoporphyrin-IX (SnPP-IX) enhanced leukocytic response. Of interest, however, liver morphology, transaminases, and bile flow as parameters of hepatocellular integrity and excretory function did not concur with reduced leukocyte numbers in the hepatic microcirculation, and revealed best organ function and tissue preservation in case of HO-1 inhibition by SnPP-IX. In contrast, hemin-treated CCl₄-exposed livers demonstrated pathologic enzyme release and cholestasis.

Conclusions

Taken together, inhibition of HO-1 in CCl₄-hepatotoxicity protected the liver, while higher HO-1 activity harmed liver tissue, most probably due to interference of the HO-1 pathway with CCl₄-dependent metabolism via cytochrome P450 and heme overload-associated toxicity.