| First Author | He CY | Year | 2012 |
| Journal | Acta Pharmacol Sin | Volume | 33 |
| Issue | 8 | Pages | 1004-12 |
| PubMed ID | 22728710 | Mgi Jnum | J:329067 |
| Mgi Id | MGI:6840080 | Doi | 10.1038/aps.2012.47 |
| Citation | He CY, et al. (2012) The dual role of osteopontin in acetaminophen hepatotoxicity. Acta Pharmacol Sin 33(8):1004-12 |
| abstractText | 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 localized 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 CYP1A2 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-alpha and IL-1alpha 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. |
