The dual role of osteopontin in acetaminophen hepatotoxicity  

作　　者：Chun-yan HE Bei-bei LIANG Xiao-yu FAN Lei CAO Rui CHEN Ya-jun GUO Jian ZHAO 

机构地区：[1]School of Medicine and School of Pharmacy, Shanghai Jiao Tong University, Shanghai 200025, China [2]International Joint OancerInstitute, The Second Military Medical University, Shanghai 200433, China [3]PLA General Hospital Cancer Center, PLA PostgraduateSchool of Medicine, Beijing 100863, China

出　　处：《Acta Pharmacologica Sinica》2012年第8期1004-1012,共9页中国药理学报（英文版）

基　　金：This work is supported in part by grants from Ministry of Sci- ence and Technology of China （2010CB945600, 2011CB966200）, National Natural Science Foundation of China, the Special Project for Infection Disease （2008ZX10002-019）, New Drug Development and Program of Shanghai Subject Chief Scien-tists （10XD1405400）.

摘　　要：Aim： Osteopontin （OPN）, a multifunctional protein, has been reported to be protoxicant in acetaminophen hepatotoxicity. In this study, the mechanisms underlying the detrimental role of OPN in acetaminophen toxicity were explored. Methods： Male C57BL/6 （wild-type, WT） and OPN-/-mice were administered with acetaminophen （500 mg/kg, ip）. After the treatment, serum transaminase （ALT）, as well as OPN expression, histology changes, oxidative stress and inflammation response in liver tissue were studied. Freshly isolated hepatocytes of WT and OPN-/- mice were prepared. Results： Acetaminophen administration significantly increased OPN protein level in livers of WT mice. OPN expression was mainly local- ized in hepatic macrophages 6 h after the administration. In OPN-/- mice, acetaminophen-induced serum ALT release was reduced, but the centrilobular hepatic necrosis was increased. In OPN-/- mice, the expression of CYP2E1 and CYPIA2 in livers was significantly increased; GSH depletion and lipid peroxidation in livers were enhanced. On the other hand, OPN-/- mice exhibited less macrophage and neutrophil infiltration and reduced expression of proinflammatory cytokines TNF-a and IL-la in livers. An anti-OPN neutralizing antibody significantly reduced acetaminophen-induced serum ALT level and inflammatory infiltration in livers of WT mice. Conclusion： OPN plays a dual role in acetaminophen toxicity： OPN in hepatocytes inhibits acetaminophen metabolism, while OPN in macrophages enhances acetaminophen toxicity via recruitment of inflammatory cells and production of proinflammatory cytokines.Aim： Osteopontin （OPN）, a multifunctional protein, has been reported to be protoxicant in acetaminophen hepatotoxicity. In this study, the mechanisms underlying the detrimental role of OPN in acetaminophen toxicity were explored. Methods： Male C57BL/6 （wild-type, WT） and OPN-/-mice were administered with acetaminophen （500 mg/kg, ip）. After the treatment, serum transaminase （ALT）, as well as OPN expression, histology changes, oxidative stress and inflammation response in liver tissue were studied. Freshly isolated hepatocytes of WT and OPN-/- mice were prepared. Results： Acetaminophen administration significantly increased OPN protein level in livers of WT mice. OPN expression was mainly local- ized in hepatic macrophages 6 h after the administration. In OPN-/- mice, acetaminophen-induced serum ALT release was reduced, but the centrilobular hepatic necrosis was increased. In OPN-/- mice, the expression of CYP2E1 and CYPIA2 in livers was significantly increased; GSH depletion and lipid peroxidation in livers were enhanced. On the other hand, OPN-/- mice exhibited less macrophage and neutrophil infiltration and reduced expression of proinflammatory cytokines TNF-a and IL-la in livers. An anti-OPN neutralizing antibody significantly reduced acetaminophen-induced serum ALT level and inflammatory infiltration in livers of WT mice. Conclusion： OPN plays a dual role in acetaminophen toxicity： OPN in hepatocytes inhibits acetaminophen metabolism, while OPN in macrophages enhances acetaminophen toxicity via recruitment of inflammatory cells and production of proinflammatory cytokines.

关 键 词：ACETAMINOPHEN OSTEOPONTIN liver HEPATOTOXICITY MACROPHAGE HEPATOCYTE CYTOKINE 

分 类 号：Q51[生物学—生物化学] TQ463.4[化学工程—制药化工]