The dual role of osteopontin in acetaminophen hepatotoxicity.
OBJECTIVE
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-α and IL-1α in livers. An anti-OPN neutralizing antibody significantly reduced acetaminophen-induced serum ALT level and inflammatory infiltration in livers of WT mice.


CONCLUSIONS
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.
School of Medicine and School of Pharmacy, Shanghai Jiao Tong University, Shanghai 200025, China.
Chun-yan
CY
He
Bei-bei
BB
Liang
Xiao-yu
XY
Fan
Lei
L
Cao
Rui
R
Chen
Ya-jun
YJ
Guo
Jian
J
Zhao
D000082:Acetaminophen / Q000633:toxicity*; D000410:Alanine Transaminase / Q000378:metabolism; D000818:Animals; D002478:Cells, Cultured; D056486:Chemical and Drug Induced Liver Injury / Q000378:metabolism* / Q000473:pathology; D022781:Hepatocytes / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D018836:Inflammation Mediators / Q000378:metabolism; D008264:Macrophages / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D053495:Osteopontin / Q000502:physiology*
D018836:Inflammation Mediators; C506896:Spp1 protein, mouse; D053495:Osteopontin; D000082:Acetaminophen; D000410:Alanine Transaminase