Hepatotoxicity and Antioxidants: An overview
The liver is responsible for several functions in the body including performing and controlling the homeostasis as well as nutrient and energy supply, metabolism and growth. It activates and inactivates exogenous and endogenous xenobiotics due to it has a defense mechanism but this sometimes inadequate, resulting in pathological conditions that influence the function and structure of the liver compartment leading to pathophysiological changes which may results in hepatotoxicity. It is the main reason for withdrawing of some drugs from marketing. Antioxidants are the substances those are present at low levels and significantly delay or prevent oxidation of the oxidizable substrate. They are one solution for controlling the hepatotoxicity. It is necessary to obtain a comprehensive article giving us overview information about hepatotoxicity and antioxidants relationship.
Keywords: Hepatotoxicity – Antioxidants - Pathophysiological changes
 Ogu C, Maxa J. Drug interactions due to cytochrome P450. ProcBaylUniv Med Cent, 2000; 13:421-423.
 Naruse K, Tang W, Makuuchi M. Artificial and bioartificial liver support: A review of perfusion treatment for hepatic failure patients. World J Gastroentero. 2007., l13: 1516-1521.
 Singh R, Kumar S, Rana AC, Sharma N.Different models of hepatotoxicity and related liver diseases: A review, IRJP, 2012., 3 (7):86-95.
 Ahsan R, Islam M, Bulbul JI, Musadik A, Haque E.Hepatoprotective activity of methanol extract of some medicinal plants against carbon tetrachloride- induced hepatotoxicity in rats Eur j sci res., 2009., 37(2):302-310.
 Reichen J. The Role of the Sinusoidal Endothelium in Liver Function . News Physiol. Sci. 1999., 14:117-121.
 Friedman SE, Grendell JH, McQuaid K, Kenneth R.Current diagnosis & treatment in gastroenterology. New York: lang medical Book / mcgraw-hill. 2008., 664-679.
 Saukkonen JJ, Cohn DL, Jasmer RM, Schenker S, Jereb JA, Nolan CM, Peloquin CA, Gordin FM, Nunes D, Strader DB, Bernardo J. venkataramanan R, Sterling TR. An Official ATS Statement: Hepatotoxicity of antituberculosis therapy. Am J RespirCrit Care Med.2006., 174: 935-952.
 Ostapowicz G, Fontan R J, Schiødt F V, Larson A, Davern TJ, Han S HB, McCashland TM, Shakil AO, Hay JE, Hynan L, Crippin JS, Blei AT, Samuel G, Reisch J, Lee WM.Results of a Prospective Study of Acute Liver Failure at 17 Tertiary Care Centers in the United States, Ann Intern Med.2002., 137:947-954.
 Jaeschke H, Gores GJ, Cederbaum AI, Hinson JA, PessayreD,Lemasters J. Mechanisms of hepatotoxicity. J Toxicol Sci.2002., 65(2):166-76.
 Subramaniam S, Han HBH, Elumalai N, Lakshmi SYS.Hepatoprotective effect of ethanolic extract of whole plant of Andrographispaniculata against CCL3-induced hepatotoxicity in rats. Comp Clin Path.2015., 24: 1-7.
 Pandit A, Sachdeva T, Bafna P. Drug-induced hepatotoxicity: A review. Journal of Applied Pharmaceutical Science 2012., 2 (5):233-243.
 Giordano, C., Rivas, J., &Zervos, X. An update on treatment of drug-induced liver injury. J ClinTransl Hepatol 2014., 2(2): 74.
 Singh D, Cho W C, Upadhyay G. Drug-induced liver toxicity and prevention by herbal antioxidants: an overview. Frontiers in physiology 2016; 6: 363.
 Subramaniam A, Pushpangadan P. Development of Phytomedicines for liver diseases. Indian J Pharmacology 1999; 31: 166-175.
 Ghori SS, Khan M, Rahman SA. Amelioration of carbon tetrachloride-and paracetamol-induced hepatotoxicity in rats by Ficusdalhousiae. Bangladesh J Pharmacol 2014;9(4):588-594.
 Rizzardini M, Zappone M, Villa P, Gnocchi P, Sironi M, Diomede L et al.Kupffer cell depletion partially prevents hepatic heme oxygenase1 messenger RNA accumulation in systemic inflammation in mice: role of interleukin 1beta. Hepatology 1998; 27:703–710.
 Muzafar AS, Manju T. Asian Liver Toxicity and its Amelioration by Natural Antioxidants - AReview J. Exp. Sci. 2018; 32(1):35-43.
 Kedderis GL. Biochemical basis of hepatocellular injury. Toxicol Pathol.1996; 24(1):77-83.
Lynch T, Price A. The effect of cytochrome P450 metabolism on drug response, interactions, and adverse effects. Am Fam Physician 2007; 76(3):391-396.
 Dienhart M, Pfeiffer K, Schagger H, Stuart RA.Formation of the yeast F1F0-ATP synthase dimeric complex does not require the ATPase inhibitor protein, Inh1. J. Biol. Chem. 2002; 277: 39289–39295.
 RavagnanL,RoumierT, KroemerG. Mitochondria the killer organelles and their weapons. J. Cell. Physiology 2002; 192:131-137.
 Murphy MP. Modulating mitochondrial intracellular location as a redox signal. Sci. Signal.2012; 5(242):39.
 Richter C.Do mitochondrial DNA fragments promote cancer and aging? FEBS Lett. 1988; 241: 1-5.
 Yakes FM, Van Houten B.Mitochondrial DNA damage is more extensive and persists longer than nuclear DNA damage in human cells following oxidative stress. Proc. Natl. Acad. Sci. USA 1997; 94(2): 514–519.
 Teschke R, Schulze J. Suspected herbal hepatotoxicity: requirements for appropriate causality assessment by the US Pharmacopeia. Drug Saf. 2012; 35(12):1091-7.
 Pessayre D,Fromenty B, Berson A, Robin MA, Letteron P, Moreau M et al.Central role of mitochondria in drug-induced liver injury. Drug Metab Rev. 2012; 44(1):34-87.
 Shayiq RM, Roberts DW, Rothstein K, Snawder JE, Benson W, Ma XM.Repeat exposure to incremental doses of acetaminophen provides protection against acetaminophen-induced lethality in mice: an explanation for high acetaminophen dosage in humans without hepatic injury. Hepatology, 1999; 29(2):451-463.
 Roberg K, Kagedal K, O¨llinger K. Microinjection of cathepsinDinducescaspase-dependent apoptosis in ﬁbroblasts. Am. J. Pathol. 2002; 161:96-98.
 Robin MA, Le Roy M, Descatoire V, Pessayer D.Plasma membrane cytochromes P450 as neoantigens and autoimmune targets in drug-induced hepatitis. J Hepatol 1997; 26: 23–30.
 Uetrecht J.New concepts in immunology relevant to idiosyncratic drug reactions: the ‘danger hypothesis’ and innate immune system. Chem Res Toxicol 1999; 12:387–95.
 Park BK, Kitteringham NR, Powell H, Pirmohamed M. Advances in molecular toxicology-towards understanding idiosyncratic drug toxicity. Toxicology 2000; 153: 39–60.
 Borgese N, Francolini M, Snapp E. “Endoplasmic reticulum architecture: structures in flux,” Current Opinion in Cell Biology 2006;18(4):358–364.
 Reddy JK. “Peroxisome proliferators and peroxisome proliferator-activated receptor-α : biotic and xenobiotic sensing,” Am J Pathol 2004;164(6):2305–232.
 Csala M, Margittai E, Banhegyi G. “Redox control of endoplasmic reticulum function,” Antioxidants & Redox Signaling, 2010; 13(1):77–108.
 Cuozzo JW, Kaiser CA. “Competition between glutathione and protein thiols for disulphide-bond formation,” Nat Cell Biol 1999; 1(3):130–135.
 Zhang K, Kaufman RJ. “From endoplasmic-reticulum stress to the inflammatory response,” Nature 2008; 454(7203): 455–462.
 Malhi H, Kaufman RJ. Endoplasmic reticulum stress in liver disease. J Hepatol 2011; 54: 795–809.
 Cnop M, Foufelle F, Velloso LA. Endoplasmic reticulum stress, obesity and diabetes. Trends Mol Med 2012; 18: 59–68.
 Cheng B, Gong H, Xiao H, Petersen RB, Zheng L, Huang K. Inhibiting toxic aggregation of amyloidogenic proteins: a therapeutic strategy for protein misfolding diseases. BiochimBiophysActa 2013; 1830: 4860–4871.
 Hoyer-Hansen M, Jäättelä M. Connecting endoplasmic reticulum stress to autophagy by unfolded protein response and calcium. Cell Death Differ 2007; 14: 1576–1582.
 Digaleh H, Kiaei M, Khodagholi F. Nrf2 and Nrf1signaling and ER stress crosstalk: implication for proteasomal degradation and autophagy. Cell Mol Life Sci 2013; 70: 4681–4694.
 Huotari J, Helenius A. Endosome maturation. EMBO J. 2011; 30:3481–3500.
 Luzio JP, Pryor PR, Bright NA. Lysosomes: fusion and function. Nat. Rev. Mol. Cell Biol. 2006; 8:622–32.
 Ruivo R, Anne C, Sagne C, Gasnier B. Molecular and cellular basis of lysosomaltransmembraneprotein dysfunction. Biochim. Biophys. Acta. 2009; 1793:636–49.
 Saftig P, Klumperman J. Lysosome biogenesis and lysosomal membrane proteins: Trafficking meets function. Nat. Rev. Mol. Cell Biol. 2000; 10:623–35.
 Kolter T, Sandhoff K.Lysosomal degradation of membrane lipids.FEBS Letters, 2010; 584:1700-1712.
 Pryor JPR, Luzio P.Delivery of endocytosed membrane proteins to the lysosome. Biochimica et BiophysicaActa (BBA)-Molecular Cell Research, 2009: 1793 (4):615-624.
 Mindell JA. "Lysosomal Acidification Mechanisms". Annual Review of Physiology.2012; 74(1): 69–86.
 Gerasimenko JV, Gerasimenko OV, Petersen OH. Membrane repair: Ca(2þ)-elicited lysosomalexocytosis.Current Biology, 2001; 11:971-974.
 Kroemer G, Jaattela M. Lysosomes and autophagy in cell death control.Nature Reviews Cancer, 2005; 5:886-897.
 Vasiljeva O, Turk B. Dual contrasting roles of cysteine cathepsins in cancer progression: apoptosis versus tumour invasion. Biochimie 2008; 90: 380-386.
 Aits S, Jaattela M.Lysosomal Cell Death at a glance.J Cell Sci, 2013; 126:1905-1912.
 Krenn MA, Schürz M, Teufl B, Uchida K, Eckl PM, Bresgen N. “Ferritin-stimulated lipid peroxidation, lysosomal leak, and macroautophagy promote lysosomal ‘metastability’ in primary hepatocytes determining in vitro cell survival,”Free Radical Biology and Medicine 2015; 80:48-58.
 Lill R, Hoffmann B, Molik S, Antonio JP, Nicole RC, Oliver S et al. “The role of mitochondria in cellular iron-sulfur protein biogenesis and iron metabolism,” Biochimica et BiophysicaActa—Molecular Cell Research 2015; 1823(9):1491–1508.
 Ashif I, Mohammad KI, Syed EH. Experimental hepatotoxicity Inducing agents: A Review, Int J Pharm Sci Res 2016; 6(11):325-335.
 Meek IL, Van MAFJ, Vonkeman HE. Non-steroidal anti-inflammatory drugs: an overview of cardiovascular risks. Pharmaceuticals. 2010; 3:2146–2162.
 Parmar SR, Vashrambhai PH, Kalia K. Hepatoprotective activity of some plants extract against paracetamol induced hepatotoxicity in rats. J Herbal Med Toxicol 2010; 4:101–6.
 Sakr SA, Abo-El-Yazid SM. Effect of fenugreek seed extract on adriamycin-induced hepatotoxicity and oxidative stress in albino rats. ToxicolInd Health 2012; 28(10):876-885.
 Talpur M, Shaikh S, Shah SA, Memon AR, Khohazo HK. Zinc sulphate in azathioprine induced hepatotoxicity -An experimental study. WJBMS 2014; 1(4):72-80.
 Singh N, Rani P, Gupta M, Goel N, Tandan N. Effects of aqueous extract of camellia sinensis on liver markers of cadmium treated rats. E3 J Biotechnol Pharm Res 2013; 4(5):89-93.
 Suganthi V, Gowri S, Gurusamy K. Hepatoprotective activity of Cayratiacarnosaon liver damage caused by lead acetate in rats. Sch Res Lib 2013; 3(2):76-79.
 Ekambaram M, Ramalingam K, Balasubramanian A. Effect of Portulacaquadrifida Linn on Mercury-Induced Hepatotoxicity in Swiss Albino Mice.Res Rev J PharmacolToxicol Stud. 2014;2:18–21.
 Clark SP, Davis MA, Ryan TP, Searfoss GH, Hooser SB. Hepatic gene expression changes in mice associated with prolonged sublethalmicrocystin exposure. ToxicolPathol 2007;35(4):594-598.
 Lanternier F, Roulot D, Bentata M, Pol S, Viard JP, Gordien E, Jeantils Vet al.GastroenterolClin Biol. 2007;31(10):822-827.
 Sanyal AJ. AGA technical review on nonalcoholic fatty liver disease. Gastroenterology 2002;123:1705–1725.
 Mauro P, Renze B, Wouter W. Enzymes. In: Tietz text book of clinical chemistry and molecular diagnostics. Carl AB, Edward R, David EB. 4th edition, Elsevier 2006; 604-616.
 Karmen A, Wroblewski F, Ladue JS."Transaminase activity in human blood". J Clin Invest 1955; 34 (1): 126–131.
 Lindblom P, Rafter I, Copley C,Andersson U, Hedberg JJ, Berg AL, et al. Isoforms of alanine aminotransferases in human tissues and serum – differential tissue expression using novel antibodies. Arch BiochemBiophys 2007; 466(1):66–77.
 Ghouri N, Preiss D, Sattar N. "Liver enzymes, nonalcoholic fatty liver disease, and incident cardiovascular disease: a narrative review and clinical perspective of prospective data". Hepatology. 2010;52 (3): 1156–1161.
 Kallei L, Hahn A, Roder VZ. Correlation between histological findings and serum transaminase values in chronic diseases of the liver. ActaMedicaScandinavika 1964;175:49-56.
 Voet D, Voet JG. Biochemistry, Biomolecules, mechanisms of enzyme action and metabolism. Electron transport and oxidative phosphorylation; 3rd edition; John Wiley and Sons, Inc. United States of America, 2004; 742-797.
 Pincus MR, Tierno PM, Fenelus M, Bowne WB, Bluth MH. Evaluation of liver function. In: McPherson RA, Pincus MR, eds. Henry's Clinical Diagnosis and Management by Laboratory Methods. 22nd ed. Philadelphia, PA: Elsevier Saunders: Chap 21, 2011.
 Thapa BR, Anuj W. Liver Function Tests and their Interpretation. Indian J Pediatr 2007;74: 663-671.
 Panteghini M, Falsetti F, Chiari E,Malchiodi A.Determinaton of Aspartate aminotransferase isoenzymes in hepatic disease. Lab J Res Lab Med 1983;10: 515-519.
 Rankin SA, Chrisitiansen A, Lee W, Banavara DS, Lopez-Hernandez A. Invited review: The application of alkaline phosphatase assays for the validation of milk product pasteurization. J Dairy Sci 2010;93(12):5538-5551.
 Arika WM, Nyamai DW, Osano KO, Ngugi MP, and Njagi ENM. Biochemical Markers of In VivoHepatotoxicity.JClinToxicol 2016; 6(2):297-305.
 Blanchard KT, Clay RJ, Morris JB. Pulmonary activation and toxicity of cyclopentadienyl manganese tricarbonyl. ToxicolApplPharmacol. 1996;136(2):280-288.
 Beaussier M., Wendum D., Schiffer E., Dumont S., Rey C., Lienhart A.et al. Prominent contribution of portal mesenchymal cells to liver fibrosis in ischemic and obstructive cholestatic injuries. Lab Invest 2007; 87(3):292-303.
 Wolf PL. Biochemical diagnosis of liver disease. Indian J ClinBiochem1999; 14(1):59-90.
 Nurbanu G, Eren G, Zeliha AB. Gamma-GlutamylTransferase Levels in Patients with Acute Ischemic Stroke, Cardiovascular Psychiatry and Neurology 2014; 1-4
 Sugiura M, Nakamura M , Ikoma Y, Yano M, Ogawa K, Matsumoto H et al. High serum carotenoids are inversely associated with serum gamma-glutamyltransferase in alcohol drinkers within normal liver function. Am J Epidemiol 2005;15:180-186.
 Wu A, Slavin G, Levi AJ. Elevated serum gamma-glutamyl-transferase (transpeptidase) and histological liver damage in alcoholism. Am J Gastroenterol1976; 65: 318-323.
 Hamed Khalili, Barham Abu Dayyeh, Lawrence SF. Assessment of Liver Function in Clinical Practice. Chronic Liver Failure 2010; 47-76
 Thomsen HF, Hardt F, Juhl E. Diagnosis of Gilbert's syndrome. Scand J Gastroenterol 1981;16:699-703.
 Beckingham IJ, Ryder SD. Clinical review ABC of diseases of liver, pancreas, and biliary system Investigation of liver and biliary disease. BMJ 2001; 322: 33-36.
 Daniel SP, Marshall MK. Evaluation of the liver: laboratory tests. Schiff’s diseases of the liver,8th edn. USA; JB Lippincott publications 1999; 205-239.
 American Gastroenterological association. American gastroenterological association medical position statement: Evaluation of liver chemistry tests. Gastroenterology 2002; 123:1364-1366.
 Sherlock S. Assessment of liver function Disease of liver and biliary system: Sheila Sherlock, 10thed, London; Blackwell science ltd, 1997; 17-32.
 Rosalki SB, Mcintyre N. Biochemical investigations in the management of liver disease. Oxford textbook of clinical hepatology, 2nd ed. New York; Oxford university press, 1999; 503-521.
 Killingsworth, L.M.. Plasma protein patterns in health and disease. Crit. Rev. Chn. Lab. Sci 1979;11,1-30.
 Bradbeer, JN, Zanelli, JM, Lindsay, PC, Pearson, J Reeve, J. Relationship between the location of osteoblastic alkaline phosphatase activity and bone formation in human iliac crest bone. J. Bone Min. I Res 1992;7, 905-912.
 Rosalki SB, Foo AY, Burlina A, Prellwitz W, Stieber P, Neumeier D et al.Multicentric evaluation of Iso-ALP test kit for measurement of bone alkaline phosphatase in serum and plasma. Clin.Chem 1993; 39,648-652.
 Aliyazicioglu Y, Deger O, Karahan C, Yildirmis S, Kucukoduk S. Reference values of cord blood transferrin, ceruloplasmin, alpha-1 antitrypsin, prealbumin, and alpha-2 macroglobulin concentrations in healthy term newborns. Turk J Pediatr 2007; 49: 52–54.
 Saito M, Seo Y, Yano Y, Miki A, Yoshida M, Azuma T. Short-term reductions in non-protein respiratory quotient and prealbumin can be associated with the long-term deterioration of liver function after transcatheter arterial chemoembolization in patients with hepatocellular carcinoma. J Gastroenterol 2012;47: 704–714.
 Liu F, Cai LY, Zhong L, Chen C, Xu F, Zhao ZX. Model for end-stage liver disease combined with serum prealbumin to predict the prognosis of patients with decompensated liver cirrhosis. J Dig Dis 2010;11: 352–357.
 Li S, Tan HY, Wang N, Zhang ZJ, Lao L, Wong CW. The role of oxidative stress and antioxidants in liver diseases. Int J MolSci 2015; 16(11): 26087-26124.
 Kunwar A, Priyadarsini KI. Free radicals, oxidative stress and importance of antioxidants in human health. J Med Allied Sci 2011; 1(2): 53-60.
 Betteridge DJ. What is oxidative stress?. Metabolism 2000;49(2): 3-8.
 Said MA, Aiman IA. Oxidative stress versus antioxidants. American Journal of Bioscience and Bioengineering 2014; 2(5): 60-71.
 Banerjee P, Jana S,Chakraborty S,Swarnakar S. Inflammation and MMPs in alcohol-induced liverdiseases and protective action of antioxidants. Indian J.Biochem. Biol 2013; 50:377–386.
 Gao B,Bataller R. Alcoholic liver disease: Pathogenesis and new therapeutic targets. Gastroenterology 2011;141:1572–1585.
 Masalkar PD, Abhang SA. Oxidative stress and antioxidant status in patients with alcoholic liver disease.Clin. Chim. Acta2005;355: 61–65.
 Beier JI, McClain CJ. Mechanisms and cell signaling in alcoholic liver disease. Biol. Chem 2010; 391:1249–1264.
 Diehl AM.Recent events in alcoholic liver disease V. Effects of ethanol on liver regeneration. Am. J.Physiol.-Gastrointest. Liver Physiol 2005;288:1–6.
 Videla LA. Oxidative stress signaling underlying liver disease and hepatoprotective mechanisms. World J.Hepatol 2009; 1: 72–78.
 Linares V, Alonso V,Albina ML, Belles M,Sirvent JJ, Domingo JL et al. Lipid peroxidationand antioxidant status in kidney and liver of rats treated with sulfasalazine. Toxicology 2009; 256: 152–156.
 Karabulut AB,Gui M,Karabulut E,Kiran TR,Ocak SG,Otlu O. Oxidant and antioxidant activity in rabbit livers treated with zoledronic acid. Transplant. Proc 2010; 42:3820–3822.
 Mladenovic D,Radosavljevic T,Ninkovic M,Vucevic D,Jesic-Vukicevic R,Todorovic V. Liverantioxidant capacity in the early phase of acuteparacetamol-induced liver injury in mice. Food Chem.Toxicol 2009;47:866–870.
 Bando I, Reus MI, Andres D,Cascales M. Endogenous antioxidant defence system in rat liver followingmercury chloride oral intoxication. J. Biochem. Mol. Toxicol 2005;19:154–161.
 Adegbesan BO,Adenuga GA. Effect of lead exposure on liver lipid peroxidative and antioxidant defensesystems of protein-undernourished rats. Biol. Trace Element Res 2007;116:219–225.
 Ozgur E, Guler G,Seyhan N. Mobile phone radiation-induced free radical damage in the liver is inhibitedby the antioxidants N-acetyl cysteine and epigallocatechin-gallate. Int. J. Radiat. Biol 2010;86: 935–945.
 Yildirim NC,Yurekli M,Yildirim N.Investigation of some antioxidant enzymes activities depending onadrenomedullintreatment and cold stress in rat liver tissue. Turk. J. Biochem 2010;35: 138–142.
 Syama S,Reshma SC,Sreekanth PJ,Varma HK,Mohanan PV. Effect of zinc oxide nanoparticles on cellular oxidative stress and antioxidant defense mechanisms in mouse liver. Environ. Toxicol. Pharmacol 2013;95:495–503.
 Zhang X,Strakovsky R, Zhou D, Zhang Y, Pan YX. A maternal high-fat diet represses the expressionof antioxidant defense genes and induces the cellular senescence pathway in the liver of male offspringrats. J. Nutr 2011;141:1254–1259.
 Dornas WC, Lima WG, Santos RC, Guerra JF, Souza MO, Silva M. et al.High dietary salt decreases antioxidant defenses in the liver of fructose-fedinsulin-resistant rats. J. Nutr. Biochem 2013;. 24: 2016–2022.
 Kohen R, Nyska A.Oxidation of biological systems: oxida-tive stress phenomena, antioxidants, redox reactions, and methods for their quantification. ToxicolPathol 2002;30:620-630.
 Mates JM.. Effects of antioxidant enzymes in the molecular control of reactive oxygen species toxicology. Toxicology2000;153:83-104.
 Bors W, Heller W, Michel C, Stettmaier K. “Flavonoids and Polyphenols: chemistry and biology” In Handbook of Antioxidants. New York, 1996;409.
 Bendich A, Olson JA.. Biological actions of carotenoids. FASEB J 1989;3:1927-1932.
 Goldman A. Melatonin, a review. Brit J ClinPharma 1995;19:258-260.
 Seifried HE, Anderson DE, Milner JA, Greenwald P. New developments in antioxidant research, Nova Science Pub-lishers Inc., Hauppauge (NY)2006..
 Herbert V.The antioxidant supplement myth. Am J ClinNutr 1994; 60:157–168.
 Galati G, Sabzevari O, Wilson JX, Brien P J.Prooxidant activity and cellular effects of the phenoxyl radicals of dietary flavonoids and other polyphenolics. Toxicology 2002; 177:91–104.
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