+1 (502) 904-2126   One Westbrook Corporate Center, Suite 300, Westchester, IL 60154, USA   Site Map
ISSN: 2574 -1241

Impact Factor : 0.548

  Submit Manuscript

Mini RewiewOpen Access

The Effects of Antioxidants on Liver Regeneration Volume 6 - Issue 4

MedihaCanbek1* and AyseOzmen Yaylaci2

  • 1Department of Biology,Eskisehir Osmangazi University,Turkey
  • 2Department of Biology,Hitit University,Turkey

Received: July 02, 2018;   Published: July 10, 2018

*Corresponding author: MedihaCanbek, Department of Biology,Eskisehir Osmangazi University,Turkey

DOI: 10.26717/BJSTR.2018.06.001375

Abstract PDF

Keywords: Liver Regeneration; Antioxidants; Partial Hepatectomy; Acute Liver Injury


The liver is an important organ that supports vital functions, including absorption of metabolites from theintestines, regulation of glucose and lipid metabolism, biotransformation of xenobiotics, secretion of hormones and maintenance of osmotic balance, etc.Impairment of hepatic functions for any reason maylead to hepatic failure if not treated appropriately [1,2]. Involving many complex events at both cellular andmolecular level, regeneration of the liver is usually divided into three phases [3].The “early phase” is whenthe regeneration starts with a rapid proliferation of the liver cells. It represents hepatocytestransition fromG0 phase to G1, where the number of newly expressed genes and level of genetic expression is greatlyelevated. The “transition phase” represents the occurrence of mitosis where the cells pass through G1-SG2-M phases during the cell cycle [4].The “termination phase” is the cellsre-entrance into the G0 phaseafter a couple of cycles of division. TGF-β plays a key role in G1 phase by halting cellular proliferation in thisphase. Integrin signaling is also known to be involved in this phase [5].

Surgical hepatic interventions for various reasons (e.g. tumor) lead to oxidative stress by disturbing freeradical or antioxidant balance. Peaking of ALT levels within first 12 hours of 70% partial hepatectomy (PH)[6]elevated MDA levels and trough amounts of GSH within first 24hours [7] shows that the amount of freeradicals increases twofolds and is further indicator of decreased free radical scavenger capacity of the liver[8].Free radicals were reported to negatively influence regeneration process by triggering several signalingpathways [9].Another model where the liver regeneration is wellstudied is the acute liver injury modelinduced by chemical substances like CCl4, since normalization of AST and ALT elevation due to oxidativestress appear to be only possible by regeneration and healing of parenchymal tissue [10].Several studies were performed to test the hypothesis that regenerative effect could be mounted byadministering various antioxidants to overcome the negative influences of free radical on hepaticregeneration. Silymarin, oneof these wellknown hepatoprotective antioxidantis used as the positivecontrol in many studies [11]. It is a polyphenolic flavonoid isolated from Sylbummarianum(milkthistle)and composed of silychristin, silydianin, silybinin, andisosilybinin flavonolignans. Silymarin was reportedto trigger regeneration in the early phase of hepatic regeneration induced by 70% partial hepatectomy [12,13]. Several studies demonstrated the efficacy of silymarin against acute liver injury [10, 14-16].

Nevertheless, Kabiri, et al. induced liver injury by thioacetamide and reported that no mitosis butlargenucleated cells were seen in silymarintreated group [6].Regenerative effect by silymarin was thought tobe resulted from increasing DNA, RNA, and protein levels by acting as RNA polymerase [10,13]. Silybinin,one of theflavonolignans of silymarin, is the main component of silymarin [17]. Sonnenbichler and Zetl(1984) reported increased mitotic activity by silybinin in hepatocytes after partial hepatectomy [18].Similar to that of silymarin [14] regenerative effect of silybinin is thought to be associated with IL-1 andTNF-α pathways [8].Quercetin, a flavonoid found in many vegetables and fruits, is a useful antioxidantstudies in various areas [19]. Quercetin (15mg/kg,orally,7 days) was reported to increase liverregeneration after partial hepatectomy, as measured by mitotic index [20]. Another study investigatedregenerative effect of quercetin (50mg/kg, 8 days) by inducing a Partial hepatectomy and CCl4 mediatedinjury, where it was reported to exert hepatoprotective effects with no cellular proliferative activity [19].Iwao, et al. reported that quercetin (200mg/kg, i.p.) that was administered just after partial hepatectomytriggered apoptosis during early phase of regeneration [21].

These different effects of quercetin in the samemodel could be explained by several factors such as dose, way, and duration of administration, and that itseffects are observed in different phases of partial hepatectomy [19]. Curcumin, a polyphenolic substanceobtained from rhizome extract of Curcuma longa plant, was reported increase GSH levels and inhibit lipidperoxidation [9,22].In the study where its effect on regeneration was investigated by Partial Heptectomymodel, curcumin (100mg/kg) was shown to inhibit regeneration in G2/M transitionrather than G1/Stransition [22]. Another study reported curcumin (100mg/kg for 7 days) to elevate GSH levels and exhibitregenerative effectas measured by MI and PCNA analyses [9]. Resveratrol is a phytoalexin known for itsantioxidant propertyand synthesized by the plants in case of stress. It was reported to show favorableeffects on regeneration process both after 70% partial hepatectomy and liver injury triggered by CCl4 [23,24]. Baicalein is a flavonoid isolated from root extract of Scutellaria baicalensis Georgi; and its regenerativeeffect was demonstrated in CCl4-induced acute liver injury by PCNA, IL-6, and TNF-α analysis [25]. Geraniol,a monoterpenoid alcoholcomprises volatile oil of some plants such as rose, lavender, and geranium. Itsantioxidant characteristic was reported in several studies. Canbek, et al. compared effects of geraniol(100mg/kg) and silymarin (100mg/kg) on liverregeneration,and reported that both substance similarlyincreased mitotic activity and exhibited regenerative effect in hepatocytes [26].

It was further suggestedthat this effect of geraniol could be attributed to IL-6 and TNF-α expression. Its regenerative effect (p.o. 100mg/kg, 200mg/kg) on liver was also reported by another study [27]. Carvacrol is a volatile oil extractedfrom Origanum onites L. (thyme),and known to have antioxidant activity [28]. The study by Uyanoglu, et al. examined the effect of carvacrol on regeneration in PH model, where carvacrol+PH group had higherlevels of mitotic and PCNA indices compared to that of PH alone group at hour 72of PH, suggesting aregenerative effect of carvacrol [29]. Ternatin is a bioflavonoid isolated from flowering tops of Egletesviscosa L. (Asteracea)and has antihepatotoxic and antiinflammatory activity. Administered for 14 days at0.1ml/kg i.p. dose to rats, its effect was examined in different timepoints in postPH regeneration setting(36h, 168h, 336h). It was reported that GSH level was markedly reduced at hour 168, and it had no effecton hepatic regeneration [30].

Melatonin is an endogenous antioxidant secreted from pineal glandandknown to exert activity on regeneration. The study by Abbasoglu, et al. (1995) reported negative effects onliver regeneration in rats whose pineal glands were removed [31].Beside its many vital functions, liver has a high regeneration capacity. Removal of a part of the liver for anyreasonor its transplantationor acute liver injury may lead to oxidative stress injuryhaving the potentialto negatively affect regeneration process. Regenerative medicine is important for replacement of injured tissue with the function alone[32,33]. Antioxidants seem to make contribution to regenerative medicine.Nonetheless, we believe that better understanding of their effects on liver regeneration warrants furthercomparison of these antioxidants with each other including differentdosages, routes of administrationandduration. Moreover, advanced molecular studies will further shed light into their modes of action.


  1. Michalopoulos GK (2013) Principles of liver regeneration and growth homeostasis. Comprehensive Physiology 3(1): 485-513.
  2. Michalopoulos GK (2014) Advances in liver regeneration. Expert Review of Gastroenterology & Hepatology 8(8): 897-907.
  3. Kurinna S, Barton MC (2011) Cascades of transcription regulation during liver regeneration. The international journal of biochemistry & cell biology 43(2): 189-197.
  4. Fausto N (2000) Liver regeneration. Journal of Hepatology 32(1): 19-31.
  5. Gilgenkrantz H, Collin De lHortet A (2018) Understanding Liver Regeneration: From Mechanisms to Regenerative Medicine. The American Journal of Pathology 188(6): 1316-1327.
  6. KabiriN, Ahangar Darabi M, Setorki M, Rafieian Kopaei M (2013) The effect of silymarin onliver injury induced by Thioacetamide in rats Hepatoprotection Thioacetamide Silymarin Rat. Journal of Herb Med Pharmacology 2(2): 29-33.
  7. Guerrieri F, Vendemiale G, Grattagliano I, Cocco T, Pellecchia G, et al. (1999) Mitochondrial oxidative alterations following partial hepatectomy. Free Radical Biology and Medicine 26(1-2): 34-41.
  8. HorváthMÉ, González Cabello R, Blázovics A, Van Der Looij M, Barta I, et al. (2001) Effect ofsilibinin andvitamin E onrestoration of cellular immune response after partial hepatectomy. Journal of Ethnopharmacology 77(2-3): 227-232.
  9. Toydemir T, Kanter M, Erboga M, Oguz S, Erenoglu C (2015) Antioxidative, antiapoptotic, andproliferative effect of curcumin on liver regeneration after partial hepatectomy in rats. Toxicologyand Industrial Health 31(2): 162-172.
  10. Bektur NE, Sahin E, Baycu C, Unver G (2016) Protective effects of silymarin againstacetaminophen-induced hepatotoxicity and nephrotoxicity in mice. Toxicology and Industrial Health 32(4): 589-600.
  11. JinYS, Lee MJ, HanW ,Sohn SI, Wang MH, et al. (2006) Antioxidant effects andhepatoprotective activityof 2,5dihydroxy-4,3′-di(β-dglucopyranosyloxy)- trans-stilbene from Morusbom by cisKoidzumi roots on CCl4-induced liver damage. Free Radical Research 40(9): 986- 992.
  12. Pradhan SC, Girish C (2006) Hepatoprotective herbal drug, silymarin from experimental pharmacology to clinical medicine. Indian Journal of Medical Research 124(5): 491-504.
  13. Savita S, Srivastava A, Sudhir S, Patnaik G, Dhawan B (1994) Effect of picroliv and silymarinon liver regeneration in rats. Indian Journal of Pharmacology 26(1) 19-22.
  14. Valenzuela A, Garrido A (1994) Biochemical bases of the pharmacological action of the flavonoid silymarin and of its structural isomer silibinin. Biological Research 27(2): 105-112.
  15. Mourelle M, Muriel P, Favari L, Franco T (1989) Prevention of CCl4- Induced Liver Cirrhosis by Silymarin. Fundamental & Clinical Pharmacology 3(3): 183-191.
  16. Favari L, PérezAlvarez V (1997) Comparative effects of colchicine and silymarin on CCl4-chronic liver damage in rats. Archives of medical research 28(1): 11-7.
  17. Vargas Mendoza N, Madrigal Santillán E, Morales González Á, Esquivel SotoJ, Esquivel Chirino C, et al. (2014) Hepatoprotective effect of silymarin. World Journal of Hepatology 6(3): 144-149.
  18. Sonnenbichler J, Zetl I (1984) Mechanism of action of silibinin. V Effect of silibinin on the synthesis of ribosomal RNA, mRNA and tRNA in rat liver in vivo. HoppeSeyler’s Zeitschriftfur physiologis che Chemie 365(5): 555-566.
  19. Barros PP, Henrique G, Gonçalves GMS, OliveiraJ C, Pagnan LG, et al. (2017) Hepatoprotective Effect of Quercetin Pretreatment Against Liver Damage and Partial Hepatectomyin Rats. Braz Arch Biol Technol 60: 1-10.
  20. Kanter M, TuncerI, Erboga, M., Atanassova P, Takir M, et al. (2016) The effects of quercetin onliver regeneration after liver resection in rats. Folia Morphologica 75(2): 179-187.
  21. IwaoK, Tsukamoto I (1999) Quercetin inhibited DNA synthesis and induced apoptosisassociatedwith increase in c-fos mRNA level and the upregulation of p21WAF1CIP1 mRNA andprotein expression during liver regeneration after partial hepatectomy. Biochimicabio physicaacta 427(1): 112-120.
  22. Seehofer D, Schirmeier A, Bengmark S, Carter J, Koch M, et al. (2009) Inhibitory Effect of Curcumin on Early Liver Regeneration Following Partial Hepatectomy in Rats. Journal of Surgical Research155(2): 195- 200.
  23. Kirimlioglu H, Ecevit A, Yilmaz S, Kirimlioglu V, Karabulut AB (2008) Effect of Resveratrol and Melatonin on Oxidative Stress Enzymes, Regeneration, and Hepatocyte Ultrastructure in Rats Subjected to 70% Partial Hepatectomy. Transplantation Proceeding 40(1): 285-289.
  24. Fan G, Tang JJ, Bhadauria M, Nirala SK, Dai F, et al. (2009) Resveratrol ameliorates carbontetrachloride-induced acute liver injury in mice. Environmental Toxicology and Pharmacology 28(3): 350-356.
  25. Huang HL, Wang YJ, Zhang QY, Liu B, Wang FY, et al. (2012) Hepatoprotective effects ofbaicale in against CCl4 -induced acute liver injury in mice. World Journal of Gastroenterology 18(45): 6605-6613.
  26. Ceyhan E, Canbek M (2017) Determining the Effects of Geraniol on Liver Regeneration Via theNuclear Factor kB Pathway After Partial Hepatectomy. Alternative Therapies in Health and Medicine 23(3): 38- 45.
  27. Hasan SK, Sultana S (2015) Geraniol attenuates 2-acetylaminofluorene induced oxidativestress, inflammation and apoptosis in the liver of wistar rats. Toxicology Mechanisms Methods 25(7): 559-573.
  28. Bayramoglu G ,Sentur kH, Bayramoglu A, Uyanoglu M, Colak S, et al. (2014) Carvacrol partiallyreverses symptoms of diabetes in STZinduced diabetic rats. Cytotechnology 66: 251-257.
  29. Canbek M, Uyanoglu M, Bayramoglu G, Senturk H, Erkasap N, et al. (2008) Effects of carvacrol on defects of ischemia-reperfusion in the rat liver. Phytomedicine 15(6-7): 447-452.
  30. MeloJUDS, Melo RB, Santos JMV Campos Júnior MM, Guimarães SB, et al. (2013) Effects of bioflavonoid ternatin on liver regeneration and oxidative stress in rats. Acta cirúrgicabrasileira 28(6): 435440.
  31. Abbasoglu O, Berker M, Ayhan A, Palaoglu S, Sayek I (1995) The effect of the pineal gland onliver regeneration in rat. Journal of Hepatology 23: 578-581.
  32. Fan F, He Z, Kong LL, Chen Q, Yuan Q, et al. (2016) Pharmacological targeting of kinases MST1 and MST2 augments tissue repair and regeneration. Science Translational Medicine 8(352): 352ra108-1-14.
  33. Mason C, Dunnill P (2008) A brief definition of regenerative medicine. Regenerative medicine 3(1): 1-5.