Abstract
Acetaminophen (APAP) overdose leads to severe hepatotoxicity. Osthole, a natural coumarin found in traditional Chinese medicinal herbs, has therapeutic potential in the treatment of various diseases. In this study, we investigated the effects of osthole against APAP-induced hepatotoxicity in mice. Mice were administered osthole (100 mg·kg-1·d-1, ip) for 3 d, then on the fourth day APAP (300 mg/kg, ip) was co-administered with osthole. The mice were euthanized post-APAP, their serum and livers were collected for analysis. Pretreatment with osthole significantly attenuated APAP-induced hepatocyte necrosis and the increases in ALT and AST activities. Compared with the mice treated with APAP alone, osthole pretreatment significantly reduced serum MDA levels and hepatic H2O2 levels, and improved liver GSH levels and the GSSG-to-GSH ratio. Meanwhile, osthole pretreatment markedly alleviated the APAP-induced up-regulation of inflammatory cytokines in the livers, and inhibited the expression of hepatic cytochrome P450 enzymes, but it increased the expression of hepatic UDP-glucuronosyltransferases (UGTs) and sulfotransferases (SULTs). Furthermore, osthole pretreatment reversed APAP-induced reduction of hepatic cAMP levels, but pretreatment with H89, a potent selective PKA inhibitor, failed to abolish the beneficial effect of osthole, whereas pretreatment with L-buthionine sulfoximine, a GSH synthesis inhibitor, abrogated the protective effects of osthole on APAP-induced liver injury, and abolished osthole-caused alterations in APAP-metabolizing enzymes. In cultured murine primary hepatocytes and Raw264.7 cells, however, osthole (40 μmol/L) did not alleviate APAP-induced cell death, but it significantly suppressed APAP-caused elevation of inflammatory cytokines. Collectively, we have demonstrated that osthole exerts a preventive effect against APAP-induced hepatotoxicity by inhibiting the metabolic activation of APAP and enhancing its clearance through an antioxidation mechanism.
Similar content being viewed by others
Log in or create a free account to read this content
Gain free access to this article, as well as selected content from this journal and more on nature.com
or
References
Bunchorntavakul C, Reddy KR . Acetaminophen-related hepatotoxicity. Clin Liver Dis 2013; 17: 587–607, viii.
James LP, McCullough SS, Knight TR, Jaeschke H, Hinson JA . Acetaminophen toxicity in mice lacking NADPH oxidase activity: role of peroxynitrite formation and mitochondrial oxidant stress. Free Radic Res 2003; 37: 1289–97.
Lee WM, Hynan LS, Rossaro L, Fontana RJ, Stravitz RT, Larson AM, et al. Intravenous N-acetylcysteine improves transplant-free survival in early stage non-acetaminophen acute liver failure. Gastroenterology 2009; 137: 856–64.
Seeff LB, Lindsay KL, Bacon BR, Kresina TF, Hoofnagle JH . Complementary and alternative medicine in chronic liver disease. Hepatology 2001; 34: 595–603.
You L, Feng S, An R, Wang X . Osthole: a promising lead compound for drug discovery from a traditional Chinese medicine (TCM). Nat Prod Commun 2009; 4: 297–302.
Wang R, Kong J, Wang D, Lien LL, Lien EJ . A survey of Chinese herbal ingredients with liver protection activities. Chin Med 2007; 2: 5.
Hoult JR, Paya M . Pharmacological and biochemical actions of simple coumarins: natural products with therapeutic potential. Gen Pharmacol 1996; 27: 713–22.
Huang RL, Chen CC, Huang YL, Hsieh DJ, Hu CP, Chen CF, et al. Osthole increases glycosylation of hepatitis B surface antigen and suppresses the secretion of hepatitis B virus in vitro. Hepatology 1996; 24: 508–15.
Okamoto T, Kawasaki T, Hino O . Osthole prevents anti-Fas antibody-induced hepatitis in mice by affecting the caspase-3-mediated apoptotic pathway. Biochem Pharmacol 2003; 65: 677–81.
Okamoto T, Yoshida S, Kobayashi T, Okabe S . Inhibition of concanavalin A-induced mice hepatitis by coumarin derivatives. Jpn J Pharmacol 2001; 85: 95–7.
Qi Z, Xue J, Zhang Y, Wang H, Xie M . Osthole ameliorates insulin resistance by increment of adiponectin release in high-fat and high-sucrose-induced fatty liver rats. Planta Med 2011; 77: 231–5.
Zhang J, Xue J, Wang H, Zhang Y, Xie M . Osthole improves alcohol-induced fatty liver in mice by reduction of hepatic oxidative stress. Phytother Res 2011; 25: 638–43.
Liu YW, Chiu YT, Fu SL, Huang YT . Osthole ameliorates hepatic fibrosis and inhibits hepatic stellate cell activation. J Biomed Sci 2015; 22: 63.
Zhang L, Jiang G, Yao F, Liang G, Wang F, Xu H, et al. Osthole promotes anti-tumor immune responses in tumor-bearing mice with hepatocellular carcinoma. Immunopharmacol Immunotoxicol 2015; 37: 301–7.
Zhang L, Jiang G, Yao F, He Y, Liang G, Zhang Y, et al. Growth inhibition and apoptosis induced by osthole, a natural coumarin, in hepatocellular carcinoma. PLoS One 2012; 7: e37865.
Yu HP, Liu FC, Tsai YF, Hwang TL . Osthole attenuates hepatic injury in a rodent model of trauma-hemorrhage. PLoS One 2013; 8: e65916.
Jaeschke H, Williams CD, Ramachandran A, Bajt ML . Acetaminophen hepatotoxicity and repair: the role of sterile inflammation and innate immunity. Liver Int 2012; 32: 8–20.
Tsai YF, Yu HP, Chung PJ, Leu YL, Kuo LM, Chen CY, et al. Osthol attenuates neutrophilic oxidative stress and hemorrhagic shock-induced lung injury via inhibition of phosphodiesterase 4. Free Radic Biol Med 2015; 89: 387–400.
Liu J, Zhang W, Zhou L, Wang X, Lian Q . Anti-inflammatory effect and mechanism of osthole in rats. Zhong Yao Cai 2005; 28: 1002–6.
Zhang ZR, Leung WN, Cheung HY, Chan CW . Osthole: a review on its bioactivities, pharmacological properties, and potential as alternative medicine. Evid Based Complement Alternat Med 2015; 2015: 919616.
Okamoto T, Kajino K, Hino O . Hepatoprotective drugs for the treatment of virus-induced chronic hepatitis: from hypercarcinogenic state to hypocarcinogenic state. Jpn J Pharmacol 2001; 87: 177–80.
Okamoto T, Kobayashi T, Yoshida S . Chemical aspects of coumarin compounds for the prevention of hepatocellular carcinomas. Curr Med Chem Anticancer Agents 2005; 5: 47–51.
Laine JE, Auriola S, Pasanen M, Juvonen RO . Acetaminophen bioactivation by human cytochrome P450 enzymes and animal microsomes. Xenobiotica 2009; 39: 11–21.
Nguyen T, Sherratt PJ, Pickett CB . Regulatory mechanisms controlling gene expression mediated by the antioxidant response element. Annu Rev Pharmacol Toxicol 2003; 43: 233–60.
Cover C, Liu J, Farhood A, Malle E, Waalkes MP, Bajt ML, et al. Pathophysiological role of the acute inflammatory response during acetaminophen hepatotoxicity. Toxicol Appl Pharmacol 2006; 216: 98–107.
Williams CD, Bajt ML, Farhood A, Jaeschke H . Acetaminophen-induced hepatic neutrophil accumulation and inflammatory liver injury in CD18-deficient mice. Liver Int 2010; 30: 1280–92.
Liao PC, Chien SC, Ho CL, Wang EI, Lee SC, Kuo YH, et al. Osthole regulates inflammatory mediator expression through modulating NF-kappaB, mitogen-activated protein kinases, protein kinase C, and reactive oxygen species. J Agric Food Chem 2010; 58: 10445–51.
Acknowledgements
This study was supported by the National Natural Science Foundation of China (No 81270944 and 81070678) and the Qinglan Project (2014) awarded to Dr Hao LI. Dr Hao LI is an associate fellow at the Collaborative Innovation Center for Cardiovascular Disease Translational Medicine.
Author information
Authors and Affiliations
Corresponding author
Supplementary information
Supplementary Information
Supplementary Figure S1–S4 (DOC 26 kb)
Rights and permissions
About this article
Cite this article
Cai, Y., Sun, W., Zhang, Xx. et al. Osthole prevents acetaminophen-induced liver injury in mice. Acta Pharmacol Sin 39, 74–84 (2018). https://doi.org/10.1038/aps.2017.129
Received:
Accepted:
Published:
Issue date:
DOI: https://doi.org/10.1038/aps.2017.129
Keywords
This article is cited by
-
The immunological mechanisms and therapeutic potential in drug-induced liver injury: lessons learned from acetaminophen hepatotoxicity
Cell & Bioscience (2022)
-
Osthole enhances the bone mass of senile osteoporosis and stimulates the expression of osteoprotegerin by activating β-catenin signaling
Stem Cell Research & Therapy (2021)
-
Osthole prevents tamoxifen-induced liver injury in mice
Acta Pharmacologica Sinica (2019)
-
Osthole inhibits triple negative breast cancer cells by suppressing STAT3
Journal of Experimental & Clinical Cancer Research (2018)
