PARP inhibition prevents acetaminophen-induced liver injury and increases survival rate in rats
Acetaminophen (APAP) overdose results in severe liver damage that may develop into acute liver failure. Recent studies have demonstrated that inhibition of poly(ADP-ribose) polymerase (PARP) decreases tissue necrosis and inflammation. We evaluated the efficacy of 3-aminobenzamide (3-AB), a PARP inhibitor, in a rodent model of APAP-induced hepatotoxicity. Materials and methods: Twenty-four Sprague-Dawley rats were divided equally into 3 experimental groups: sham group, APAP group, and APAP + 3-AB group. In the experimental treatment groups APAP was administered orally at 1 g/kg and, in the APAP + 3-AB group, 3-AB was administered intraperitoneally at a dose of 20 mg/kg exactly 1 h after APAP treatment. Surviving animals were euthanized 48 h after initial APAP administration. Blood samples and liver tissues were collected for histopathological and biochemical analysis. Results: A panel of oxidative stress parameters, as well as serum aspartate aminotransferase, alanine aminotransferase, neopterin, and nitrite/nitrate and histological injury scores, were significantly reduced among the APAP + 3-AB treatment group relative to the group treated with APAP alone (P < 0.05, APAP vs. APAP + 3-AB). Conclusion: The present study demonstrates that 3-AB inhibited APAP-induced hepatic injury and reduced neopterin levels. Results of the present study indicate that PARP inhibitors may be an effective adjuvant therapy resulting in improved outcomes in APAP-induced hepatotoxicity.
PARP inhibition prevents acetaminophen-induced liver injury and increases survival rate in rats
Acetaminophen (APAP) overdose results in severe liver damage that may develop into acute liver failure. Recent studies have demonstrated that inhibition of poly(ADP-ribose) polymerase (PARP) decreases tissue necrosis and inflammation. We evaluated the efficacy of 3-aminobenzamide (3-AB), a PARP inhibitor, in a rodent model of APAP-induced hepatotoxicity. Materials and methods: Twenty-four Sprague-Dawley rats were divided equally into 3 experimental groups: sham group, APAP group, and APAP + 3-AB group. In the experimental treatment groups APAP was administered orally at 1 g/kg and, in the APAP + 3-AB group, 3-AB was administered intraperitoneally at a dose of 20 mg/kg exactly 1 h after APAP treatment. Surviving animals were euthanized 48 h after initial APAP administration. Blood samples and liver tissues were collected for histopathological and biochemical analysis. Results: A panel of oxidative stress parameters, as well as serum aspartate aminotransferase, alanine aminotransferase, neopterin, and nitrite/nitrate and histological injury scores, were significantly reduced among the APAP + 3-AB treatment group relative to the group treated with APAP alone (P < 0.05, APAP vs. APAP + 3-AB). Conclusion: The present study demonstrates that 3-AB inhibited APAP-induced hepatic injury and reduced neopterin levels. Results of the present study indicate that PARP inhibitors may be an effective adjuvant therapy resulting in improved outcomes in APAP-induced hepatotoxicity.
___
- Yaman H, Isbilir S, Cakir E, Uysal B. Current issues with paracetamol induced toxicity. J Exp Integr Med 2011; 1: 165– 166.
- Murali A, Ashok P, Madhavan H. Hepatoprotective effect of Hemidesmus indicus var. pubescens leaf extract on paracetamol induced hepatic damage. Medicinal Chemistry & Drug Discovery 2012; 3: 103–115.
- Farber JL, Leonard TB, Kyle ME, Nakae D, Serroni A, Rogers SA. Peroxidation-dependent and peroxidation-independent mechanisms by which acetaminophen kills cultured rat hepatocytes. Arch Biochem Biophys 1980; 267: 640–650.
- Gerson RJ, Casini A, Gilfor D, Serroni A, Farber JL. Oxygen- mediated cell injury in the killing of cultured hepatocytes by acetaminophen. Biochem Biophys Res Commun 1980; 126: 1129–1137.
- Pacifici GM, Back DJ. Sulphation and glucuronidation of paracetamol in human liver: assay conditions. Biochem Pharmacol 1988; 37: 4405–4407.
- Nelson SD. Mechanisms of the formation and disposition of reactive metabolites that can cause acute liver injury. Drug Metab Rev 1995; 27: 147–177.
- Anbarasu C, Rajkapoor B, Kalpana J. Protective effect of Pisonia aculeata on paracetamol induced hepatotoxicity in rats. J Exp Integr Med 2011; 1: 167–172.
- Nelson SD. Molecular mechanisms of the hepatotoxicity caused by acetaminophen. Semin Liver Dis 1990; 10: 267–278.
- Cohen SD, Khairallah EA. Selective protein arylation and acetaminophen-induced hepatotoxicity. Drug Metab Rev 1997; 29: 59–77.
- Qiu Y, Benet LZ, Burlingame AL. Identification of hepatic protein targets of the reactive metabolites of the non-hepatotoxic regioisomer of acetaminophen, 3′-hydroxyacetanilide, in the mouse in vivo using two-dimensional gel electrophoresis and mass spectrometry. Adv Exp Med Biol 2001; 500: 663–673.
- Tirmenstein, MA, Nelson SD. Subcellular binding and effects on calcium homeostasis produced by acetaminophen and a nonhepatotoxic regioisomer, 3′-hydroxyacetanilide, in mouse liver. J Biol Chem 1989; 264: 9814–9819.
- Meyers LL, Beierschmitt WP, Khairallah EA, Cohen SD. Acetaminophen-induced inhibition of mitochondrial respiration in mice. Toxicol Appl Pharmacol 1988; 93: 378–387.
- Ramsay RR, Rashed MS, Nelson SD. In vitro effects of acetaminophen metabolites and analogs on the respiration of mouse liver mitochondria. Arch Biochem Biophys 1989; 273: 449–457.
- Jaeschke H. Glutathione disulfide formation and oxidant stress during acetaminophen-induced hepatotoxicity in mice in vivo: The protective effect of allopurinol. J Pharmacol Exp Ther 1990; 255: 935–941.
- Knight TR, Kurtz A, Bajt ML, Hinson JA, Jaeschke H. Vascular and hepatocellular peroxynitrite formation during acetaminophen-induced liver injury: role of mitochondrial oxidant stress. Toxicol Sci 2001; 62: 212–220.
- Knight TR, Ho YS, Farhood A, Jaeschke H. Peroxynitrite is a critical mediator of acetaminophen hepatotoxicity in murine livers: protection by glutathione. J Pharmacol Exp Ther 2002; 303: 468–475.
- Adams ML, Pierce RH, Vail ME, White CC, Tonge RP, Kavanagh TJ, Fausto N, Nelson SD, Bruschi SA. Enhanced acetaminophen hepatotoxicity in transgenic mice overexpressing BCL-2. Mol Pharmacol 2001; 60: 907–915.
- Knight TR, Jaeschke H. Acetaminophen-induced inhibition of Fas receptor-mediated liver cell apoptosis: Mitochondrial dysfunction versus glutathione depletion. Toxicol Appl Pharmacol 2002; 181: 133–141.
- Kon K, Kim JS, Jaeschke H, Lemasters JJ. Mitochondrial permeability transition in acetaminophen-induced necrotic and apoptotic cell death to cultured mouse hepatocytes. Hepatology 2004; 40: 1170–1179.
- Ray SD, Sorge CL, Raucy JL, Corcoran GB. Early loss of large genomic DNA in vivo with accumulation of Ca2+ in the nucleus during acetaminophen-induced liver injury. Toxicol Appl Pharmacol 1990; 106: 346–351.
- Ray SD, Kamendulis LM, Gurule MW, Yorkin RD, Corcoran GB. Ca2+ antagonists inhibit DNA fragmentation and toxic cell death induced by acetaminophen. FASEB J 1993; 7: 453–463.
- Shen W, Kamendulis LM, Ray SD, Corcoran GB. Acetaminophen-induced cytotoxicity in cultured mouse hepatocytes: effects of Ca2+-endonuclease, DNA repair, and glutathione depletion inhibitors on DNA fragmentation and cell death. Toxicol Appl Pharmacol 1992; 112: 32–40.
- Gujral JS, Knight TR, Farhood A, Bajt ML, Jaeschke H. Mode of cell death after acetaminophen overdose in mice: apoptosis or oncotic necrosis? Toxicol Sci 2002; 67: 322–328.
- Lawson JA, Fisher MA, Simmons CA, Farhood A, Jaeschke H. Inhibition of Fas receptor (CD95)-induced hepatic caspase activation and apoptosis by acetaminophen in mice. Toxicol Appl Pharmacol 1999; 156: 179–186.
- Jahr S, Hentze H, Englisch S, Hardt D, Fackelmayer FO, Hesch RD, Knippers R. DNA fragments in the blood plasma of cancer patients: quantitations and evidence for their origin from apoptotic and necrotic cells. Cancer Res 2001; 61: 1659– 1665.
- Liaudet L. Poly(adenosine 5’-diphosphate) ribose polymerase activation as a cause of metabolic dysfunction in critical illness. Curr Opin Clin Nutr Metab Care 2002; 5: 175–184.
- Pacher P, Beckman JS, Liaudet L. Nitric oxide and peroxynitrite in health and disease. Physiol Rev 2007; 87: 315–424.
- Erdelyi K, Bakondi E, Gergely P, Szabo C. Pathophysiologic role of oxidative stress-induced poly(ADP-ribose) polymerase-1 activation: focus on cell death and transcriptional regulation. Cell Mol Life Sci 2005; 62: 751–759.
- Cover C, Fickert P, Knight TR, Fuchsbichler A, Farhood A, Trauner M, Jaeschke H. Pathophysiological role of poly(ADP-ribose) polymerase (PARP) activation during acetaminophen-induced liver cell necrosis in mice. Toxicol Sci 2005; 84: 201–208.
- Kroger H, Ehrlich W, Klewer M, Gratz R, Dietrich A, Miesel R. The influence of antagonists of poly(ADP- ribose) metabolism on acetaminophen hepatotoxicity. Gen Pharmacol 1996; 27: 167–170.
- Oztas E, Guven A, Türk E, Uysal B, Akgül EO, Cayci T, Ersoz N, Korkmaz A. 3-Aminobenzamide, a poly ADP ribose polymerase inhibitor, attenuates renal ischemia/reperfusion injury. Ren Fail 2009; 31: 393–399.
- Yasar M, Uysal B, Kaldirim U, Oztas Y, Sadir S, Ozler M, Topal T, Coskun O, Kilic A, Cayci T et al. Poly(ADP-ribose) polymerase inhibition modulates experimental acute necrotizing pancreatitis-induced oxidative stress, bacterial translocation and neopterin concentrations in rats. Exp Biol Med 2010; 235: 1126–1133.
- Graziani G, Szabó C. Clinical perspectives of PARP inhibitors. Pharmacol Res 2005; 52: 109–118.
- Purnell MR, Whish WJ. Novel inhibitors of poly(ADP- ribose) synthetase. Biochem J 1980; 185: 775–777.
- Karlberg T, Hammarström M, Schütz P, Scensson L, Schüler H. Crystal structure of the catalytic domain of human PARP2 in complex with PARP inhibitor ABT-888. Biochemistry 2010; 49: 1056–1058.
- Chattopadhyay RR, Sarkar SK, Ganguly S, Banerjee RN, Basu TK, Mukherjee A. Hepatoprotective activity of Azadirachta indica leaves on paracetamol induced hepatic damage in rats. Indian J Exp Biol 1992; 30: 738–740.
- Lowry OH, Rosebrough NJ, Farr AL, Randall RJP. Protein measurement with the Folin phenol reagent. J Biol Chem 1951; 193: 265–275.
- Ohkawa H, Ohishi H, Yagi K. Assay for lipid peroxides in animal tissues by thiobarbituric reaction. Anal Biochem 1979; 95: 351–358.
- Durak I, Yurtarslani Z, Canbolat O, Akyol O. A methodological approach to superoxide dismutase (SOD) activity assay based on inhibition of nitroblue tetrazolium (NBT) reduction. Clin Chim Acta 1993; 214: 103–104.
- Paglia DE, Valentine WN. Studies on the quantitative and qualitative characterization of erythrocyte glutathione peroxidase. J Lab Clin Med 1967; 70: 158–169.
- Alrashed M, Abougoush M, Akgul EO, Erbil MK. Detection method of serum and urine neopterin levels by high performance liquid chromatography and clinical applications. Gulhane Medical Journal 2002; 44: 273–277.
- Koca K, Yurttas Y, Bilgic S, Cayci T, Topal T, Durusu M, Kaldirim U, Akgul EO, Ozkan H, Yanmis I et al. Effect of preconditioned hyperbaric oxygen and ozone on ischemia- reperfusion induced tourniquet in skeletal bone of rats. J Surg Res 2010; 164: 83–89.
- Gul H, Uysal B, Cakir E, Yaman H, Macit E, Yildirim AO, Eyi YE, Kaldirim U, Oztas E, Akgul EO et al. The protective effects of ozone therapy in a rat model of acetaminophen-induced liver injury. Environ Toxicol Pharmacol 2012; 34: 81–86.
- Davidson DG, Eastham WN. Acute liver necrosis following overdose of paracetamol. Br Med J 1966; 5512: 497–499.
- Dixon MF, Nimmo J, Prescott LF. Experimental paracetamol- induced hepatic necrosis: a histopathological study. J Pathol 1971; 103: 225–229.
- Schiodt FV, Ott P, Christensen E, Bondesen S. The value of plasma acetaminophen half-life in antidote-treated acetaminophen overdosage. Clin Pharmacol Ther 2002; 71: 221–225.
- Boyer TD, Rouff SL. Acetaminophen-induced hepatic necrosis and renal failure. JAMA 1971; 218: 440–441.
- Prescott LF, Roscoe P, Wright N, Brown SS. Plasma-paracetamol half-life and hepatic necrosis in patients with paracetamol overdosage. Lancet 1971; 1: 519–522.
- Laskin DL. Parenchymal and nonparenchymal cell interactions in hepatotoxicity. Adv Exp Med Biol 1990; 283: 499–505.
- Laskin DL. Role of macrophages and endothelial cells in hepatotoxicity. In: Billiar TR, Curran RD, editors. Hepatocyte and Kupffer Cell Interactions. Boca Raton, FL, USA: CRC Press; 1992. pp. 147–168.
- Billiar TR, Curran RD, Williams DL, Kispert PH. Liver nonparenchymal cells are stimulated to provide interleukin 6 for induction of the hepatic acute-phase response in endotoxemia but not in remote localized inflammation. Arch Surg 1992; 127: 31–37.
- Ramadori G, Van Damme J, Rieder H, Meyer zum Buschenfelde KH. Interleukin 6, the third mediator of acute-phase reaction, modulates hepatic protein synthesis in human and mouse. Comparison with interleukin 1 beta and tumor necrosis factor- alpha. Eur J Immunol 1988; 18: 1259–1264.
- Blazka ME, Wilmer JL, Holladay SD, Wilson RE, Luster MI. Histopathology of acetaminophen-induced liver changes: role of interleukin 1 alpha and tumor necrosis factor alpha. Toxicol Pathol 1996; 24: 181–189.
- Bruss M, Homann J, Molderings GJ. Dysferlinopathy as an extrahepatic cause for the elevation of serum transaminases. Medizinische Klinik 2004; 99: 326–329 (article in German with English abstract).
- Huang L, Heinloth AN, Zeng ZB, Paules RS, Bushel PR. Genes related to apoptosis predict necrosis of the liver as a phenotype observed in rats exposed to a compendium of hepatotoxicants. BMC Genomics 2008; 9: 288.
- Demirbas S, Cakir E, Akgul EO, Seyrek M, Cayci T, Kurt YG, Uysal B, Aydin I, Kurt B, Yaman H et al. Elevated serum neopterin levels in acetaminophen-induced liver injury. Environ Toxicol Pharmacol 2011; 31: 165–170.
- Kaufmann P, Tilz GP, Demel U, Wachter H, Kreijs GJ, Fuchs D. Neopterin plasma concentrations predict the course of severe acute pancreatitis. Clin Chem Lab Med 1998; 36: 29–34.