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Medicinal plants with hepatoprotective potentials against carbon tetrachloride-induced toxicity: a review
Egyptian Liver Journal volume 11, Article number: 88 (2021)
Carbon tetrachloride (CCl4) is a well-characterized hepatotoxic agent. With rising cases of liver diseases, the identification, assessment, and development of hepatoprotective agents from plants source has become imperative.
With arrays of literature on plants with hepatoprotective potentials, this review sourced published literatures between 1998 and 2020 and systematically highlighted about 92 medicinal plants that have been reported to protect against CCl4-induced liver injury in animal models. The results show that herbal plants provide protection for the liver against CCl4 by downregulation of the liver marker enzymes and activation of antioxidant capacity of the liver cells with the restoration of liver architecture. We also provided the traditional and accompanying pharmacological uses of the plants. A variety of phytochemicals mostly flavonoids and polyphenols compounds were suggested to offer protection against liver injuries.
It can be concluded that there are a variety of phytochemicals in plant products with hepatoprotective activity against CCl4-induced toxicity in animal models.
The liver being an important organ is often exposed to array of threats . Injury to the liver can lead to deterioration of its functions and may culminate in organ failure . The likely risk factors for the development of the liver diseases have been suggested to include pathogenic microorganisms and viruses, hepatotoxins, overdose and duration of drugs, obesity and malnutrition, alcohol, autoimmune disorders, type-2 diabetes, and genetic factors . The diseases of the liver are of public health concern because orthodox remedies for liver diseases produce limited results with attendant side effects. As such, utilization of complementary and alternative herbal medicine has attracted research interest for novel plausible hepatoprotective agents capable of ameliorating or reversing liver injury with little side effects [3, 4]. Over the years, this search has gained impetus with many studies focusing on hepatoprotective potentials of plant drugs.
Carbon tetrachloride (CCl4) is a known hepatotoxicant in humans and animal models . It has been successfully used in hepatotoxicity research as a model and to appraise hepatoprotective agents [6, 7]. With reports on the rise of liver diseases and numerous literature reports on plants with potential hepatoprotective activity, this review highlighted the mechanism of CCl4 toxicity, the significance, effectiveness, and underlying mechanisms of herbal plant extracts on CCl4-induced toxicity in experimental animal models.
Insight on the mechanism of carbon tetrachloride hepatotoxicity
Prior to the Montreal Protocol, CCl4 was formerly and widely used as a fire suppressant, as a precursor to refrigerants, propellants for aerosol cans, as a cleaning agent, a widely used solvent in organic chemistry, as a pesticide, and anesthetics [8, 9]. However, it is rarely used today because of adverse health effects and environmental safety concerns. Symptoms associated with acute inhalation of low–medium doses include headache, weakness, lethargy/general anesthesia, nausea, vomiting, and respiratory arrest. For medium to high oral exposure, the liver is known to be the primary site of CCl4-induced toxicity beginning with acute but progressive centrilobular injury that may culminate in cell death .
Due to the complex nature of CCl4-induced liver damage, there have emerged several independent mechanisms to explain each of the facets of the associated changes. The interrelationship among diverse mechanisms proposed for each of these associated changes has not been well-established/outlined. This is primarily because early and later changes associated with the hepatotoxic development have been mixed up. As a result, a harmonized understanding of the intricate mechanisms involved in hepatic damage has become partly elusive. However, this has not obscured the following experimental deductions (Fig. 1):
Changes in endoplasmic reticulum (ER) function due to decrease in glucose-6 phosphatase , which may not be unconnected with CCl4-induced glycogen depletion and attendant protection from carbohydrate-rich diets [12, 13]. Besides, CCl4-induced disruption and disassociation of polyribosomes from ER alters its anabolic function as manifested in decreased incorporation of amino acids into proteins such as albumin and fibrinogen . Additionally, CCl4-induced hypomethylation of 2′-O-ribose moieties in rRNA might have resulted from transient increase in cytosolic Ca2+. This increase may activate the selective destruction of rRNA methylases via the action of demethylases or proteases. Overall, the protein synthetic function of ER in the centrilobular region may be hampered with an attendant defects in the ability of the liver to effectively respond to additional insults .
Calcium homeostasis underlies some aspects of CCl4 hepatotoxicity (plasma membrane blebbing and fatty accumulation- steatosis); CCl4 may elicit dramatic redistribution of intracellular Ca2+ stores, albeit no total cellular change . Calcium ion (Ca2+) homeostasis is maintained by 3 mechanisms: (i) Ca2+ extrusion by plasma membrane ATPase, (ii) Ca2+ sequestration by mitochondria, and (iii) Ca2+ sequestration by liver ER. So, CCl4 may cause decreased Ca2+ sequestration by ER and mitochondria, decreased extrusion by plasma membrane ATPase, as well as blockage of gap junctional intercellular communication may favor increase cytosolic Ca2+. An ATP-dependent Ca2+ sequestration by hepatic ER has been shown to be disrupted by CCl4 . Endoplasmic reticulum membrane permeability may also be altered, being one indicator of impending cell death .
Rapid destruction/decrease in cytochrome P450 in centrilobular regions (suggesting that CCl4 was metabolized by ER mixed-function oxidase system), which is orchestrated by low levels of reduced glutathione (GSH) and low oxygen tension. In turn, low level oxygen tension may limit competition between O2 and CCl4 for cytochrome P450 binding (i.e., CCl4 may readily bind to cytochrome P450).
Metabolic products [trichloromethyl (CCl3*) or peroxytrichloromethyl (CCl3-OO*) free radical] elicit damage: lipid peroxidation of vulnerable unsaturated fatty acids in membrane phospholipids and destruction of haem moiety of cytochrome P450.
Blockage of gap junctional communication by CCl4 thereby shutting down intercellular communication.
Changes in mitochondrial function: disruption of oxidative phosphorylation due partly to chelation of calcium .
Making sense out of experimental deductions
The hepatic biotransformation of CCl4 primarily involves metabolic activation to transient reactive intermediates. Under low oxygen partial pressure, cytochrome P450 catalyzes the reductive de-halogenation of CCl4 resulting in predominant formation of CCl3* and CHCl* radicals [18, 19]. These reactive intermediates may bind covalently to cellular components (membranes, microsomes) and impinge on mostly lipid metabolism (increased synthesis, decreased transport out of the hepatocyte) thereby culminating in hepatic steatosis (fatty liver) [20, 21].
Dianzani  reported that covalent modification of lipoproteins occurs prior to their decreased transport out of hepatocytes. Intracellular maturation of lipoproteins in the Golgi apparatus is dependent on galactosylation which is catalyzed by glucosyl- and galactosyltransferases . The CCl4-induced damage of Golgi apparatus and eventual reduction in the activities of these enzymes may explain the observed decrease in lipoprotein secretion associated with CCl4 intoxication. Thus, CCl4-induced inhibition of lipoprotein secretion, and its attendant hepatic steatosis mainly result from covalent binding of CCl4 metabolites to cell constituents, but not due to lipid peroxidation.
Under high oxygen partial pressure, however, CCl3* may interact with oxygen to form CCl3-OO*. The peroxy radicals may elicit the peroxidation of unsaturated fatty acids especially in membrane phospholipids of intracellular and plasma membranes . Some of the lipid peroxidative products may inflict further damage leading to increased membrane permeability and a comprehensive loss in membrane integrity . Thus, both covalent binding of CCl4 metabolites and lipid peroxidation work in tandem to elicit the hallmark of damage seen in CCl4-induced hepatotoxicity.
The consequences of loss of membrane integrity are enormous and may lead to cascade of events culminating in liver necrosis. These events may include disturbed Ca2+ homeostasis/dramatic redistribution of Ca2+ in hepatocytes, leakage/efflux of K+, and influx of Na+ [10, 26].
Beside the peroxidative action, CCl4-derived free radicals and their attendant oxidative stress have been shown to enhance NF-kB expression, which in turn initiates the synthesis of cytotoxic cytokines, which may be partly responsible for liver injury . Tumor necrosis alpha (TNF-α) has been implicated in CCl4-induced hepatocellular damage . At lower doses of CCl4, inflammatory responses prevail. Healthy hepatocytes are insensitive to tissue necrosis factor alpha (TNF-α) action, but become sensitive once protein and RNA synthesis are inhibited .
Summarily, CCl4 hepatotoxicity may be due to a combination of factors such as the thorough inhibition of protein synthesis, the severe derailment of intracellular Ca2+ sequestration, and the effect on membrane integrity. These factors may result and progress through a series of steps that contribute to various extents to the ultimate damage: reductive dehalogenation, covalent binding of resulting radicals; inhibition of protein synthesis (in particular, apolipoprotein synthesis), assembly, packaging and release of VLDL and HDL, fat accumulation; formation of CCl3* and CHCl2* and CCl3-OO* radicals, lipid peroxidation, membrane damage, the severe derailment of intracellular Ca2+ sequestration, apoptosis, and fibrosis [10, 30, 31].
Traditional plants with anti-hepatotoxic potential
In this review, numerous experimental studies on the medicinal plants effectiveness to ameliorate CCl4-induced hepatotoxicity in animal models were presented. The botanical names, ethnopharmacological and pharmacological uses of plants traditionally used to treat liver-related diseases were presented in Table 1. The comprehensive details on in vivo studies of medicinal plants with hepatoprotection against CCl4-induced hepatotoxicity alongside the active phytochemicals and their probable mechanisms of action are presented in Table 2.
For about three decades, extracts from different natural products have been identified to be hepatoprotective at varied doses against CCl4-induced toxicity by reducing oxidative stress on liver enzymes. The findings from this review show that only few studies tested these natural products on hepatic cell lines (Table 2). Without separating the whole extract to identify the active components, a large number of hepatoprotective products will increase without corresponding clinical relativity . There is an urgent need to study individual components of the plant extract especially in experimental animal models. The major drawback of herbal medicine is its potential hepatotoxicity in man which could cause acute to chronic liver injury with underlining mechanism of toxicity not clearly understood due to factors such as the synergistic and multi-organ targeted nature of the various components [124,125,126,127].
The protection provided by herbal plants against CCl4-induced hepatotoxicity is basically due to the inhibitory nature of the phytochemicals present in them [70, 101]. These phytochemicals are able to inhibit the microsomal enzymes to restrict the generation of free radicals and stop lipid peroxidation through its antioxidant ability . They can also enhance the regeneration of liver cells, radical scavenging, and stimulation of the anti-inflammatory ability of the liver cells against the inflammation induced by CCl4 .
The treatment of the animal models with these herbal extracts showed beneficial effects through several biochemical and histological results. From the results in Table 2, it is clear that these plants extract downregulated serum liver marker enzymes like aspartate transaminase (AST), alanine transaminase (ALT), alkaline phosphatase (ALP), total bilirubin, and malondialdehyde (MDA) while upregulating the activity of antioxidant enzymes and total protein. The medicinal plants also downregulated the inflammatory markers expression in the hepatic cells. Some of these reported studies confirmed the hepatoprotective effectiveness of these medicinal plant products through histological reports [43, 54]. This review also reported numerous phytochemicals with possible hepatoprotective potentials ranging from flavonoids (quercetin, kaempferol), phenols, sobatum, courmarins, gallic acid, rutin, alkaloids, saponins, vitamin C, caffeic acid, etc. This review presented a number of plant species with ethnopharmacological relevance in the treatment of liver injury and their medicinal/pharmacological uses from literature.
We, therefore, conclude that there are a variety of phytochemicals in plant products with hepatoprotective activity against CCl4-induced toxicity by downregulation of liver marker enzymes, and activation of antioxidative capacity of the liver cells that leads to the restoration of the liver architecture.
There is need to validate the efficacy of some of the reported active components which can be likely candidate for therapeutic purposes. Research should move from whole plant extract experiment to isolation of bioactive components and testing the extract on culture cell lines.
Availability of data and materials
The datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request.
Glutathione S-transferase alpha
Thiobarbituric acid reactive substance
- H2O2 :
- TNF-α :
Tumor necrosis factor alpha
Nuclear factor-kappa B
Inducible nitric oxide synthase
Nuclear factor erythroid-2-related factor 2
Hepatic growth factor-beta 1
Hepatic toll-like receptor 4
P38 mitogen-activated protein kinase
Extracellular signal-regulated kinase
C-jun N-terminal kinase
A phase II enzyme
- Vit. A:
- Vit. E:
- Vit. C:
Central nervous system
Zhang X, Feng J, Su S, Huang L (2020) Hepatoprotective effects of Camellia nitissima aqueous ethanol extract CCl4-induced acute liver injury in SD rats related to Nrf2 and NF-kB signaling. Pharm Biol 5(1):239–246
Wang S, Luan JJ, Lv XW (2019) Inhibition of endoplasmic reticulum stress attenuated ethanol-induced exosomal miR-122 and acute liver injury in mice. Alcohol Alcohol 54:465–471
Chao J, Lee M-S, Amagaya S, Liao J-W, Ho L-K, Peng W-H (2009) Hepatoprotective effect of Shidagonlo on acute liver injury induced by carbon tetrachloride. Am J Chin Med 37(6):1085–1097
Zhang H, Yu C-H, Jiang Y-P, Peng C, He K, Tang J-Y, Xin H-L (2012) Protective effects of polydatin from Polygonum cuspidatum against carbon tetrachloride-induced liver injury in mice. PLoS One 7(9):e46574. https://doi.org/10.1371/Journal.pone.0046574
Batool R, Khan MR, Majid M (2017) Euphobia dracunculoides L. abrogates carbon tetrachloride induced liver and DNA damage in rats. BMC Complement Altern Med 17:23. https://doi.org/10.1186/s12906-01744-x
Bakr RO, El-Naa MM, Zaghlou SS, Omar MM (2017) Profile of bioactive compounds in Nymphaea alba L. leaves growing in Egypt: hepatoprotective, antioxidant and anti-inflammatory activity. BMC Complement Altern Med 17:52. https://doi.org/10.1186/s12906-017-156/-2
Hsouna AB, Dhibi S, Dhifi W, Saad RB, Brini F, Hfaidh N, da Silva Almeida JRG, Mnif W (2020) Lobularia maritima leave extract, a neutraceutical agent with antioxidant activity, protects against CCl4-induced liver injury in mice. Drug Chem Toxicol. https://doi.org/10.1080/01480545.2020.1742730
Jones I (1983) Chloroform anaesthesia in Liverpool. Anaesthesia 38:578–580
Agency for Toxic Substances and Disease Registry (ATSDR) (2005) Toxicological profile for carbon tetrachloride. U.S. Department of Health and Human Services, Public Health Service, Atlanta
Clawson GA (1989) Mechanism of carbon tetrachloride toxicity. Pathol Immunopathol Res 8:104–112
Recknagel R, Lombardi B (1961) Studies of biochemical changes in subcellular particles of rat liver and their relationship to a new hypothesis regarding the pathogenesis of carbon tetrachloride fat accumulation. J Biol Chem 236:564–569
Judah J (1969) Biochemical disturbances in liver injury. Br Med Bull 25:274–277
de Vries J (1983) Induction and prevention of biochemical disturbances in hepatic necrosis. Trends Pharmacol Sci 4:393–394
Smuckler E, Iseri O, Bendit E (1962) An intracellular defect in protein synthesis induced by carbon tetrachloride. J Exp Med 116:55–72
Moore L, Chen J, Knapp H, Landon E (1975) Energy-dependent calcium sequestration activity in rat liver microsomes. J Biol Chem 250:4562–4568
Fulceri R, Benedetti A, Comporti M (1984) On the mechanisms of the inhibition of calcium sequestering activity of liver microsomes in bromothrichloromethane intoxication. Res Commun Chem Pathol Pharmacol 46:235–243
Christie G, Judah J (1954) Mechanism of action of CCl4 on liver cells. Proc R Soc Lond Ser 142:241–257
De Groot H, Littauer A, Hugo-Wissemann D, Wissemann P, Noll T (1988) Lipid peroxidation and cell viability in isolated hepatocytes in a redesigned oxystat system: Evaluation of the hypothesis that lipid peroxidation , preferentially induced at low oxygen partial pressure, is decisive for CCl4 liver cell injury. Arch Biochem Biophys 264:591–599
Masuda Y, Nakamura Y (1990) Effects of oxygen deficiency and calcium omission on carbon tetrachloride hepatotoxicity in isolated perfused livers from phenobarbital-pretreated rats. Biochem Pharmacol 40:1865–1876
Kiezcka H, Kappus H (1980) Oxygen dependence of CCl4-induced lipid peroxidation in vitro and in vivo. Toxicol Lett 5:191–196
Dianzani MU, Poli G (1985) Lipid peroxidation and haloalkylation in CCl4-induced liver injury. In: Poli G, Cheeseman KH, Dianzani MU, Slater TF (eds) Free Radicals in Liver Injury. IRL Press, Oxford
Dianzani MU (1984) Lipid peroxidation and haloalkylation: Two distinct mechanisms for CCl4 -induced liver damage. In: Calandra S, Carulli N, Salvioli G (eds) Liver and Lipid Metabolism. Excerpta Medica, Elsevier, Amsterdam, New York, Oxford
Marinari UM, Pronzato MA, Cottalasso D, Zicca-Cadoni A, Nanni G, Poli G, Chiarpotto E, Albano E, Biasi F, Dianzani MU (1985) CCl4-induced early functional impairments of rat liver Golgi apparatus. In: Poli G, Cheeseman KH, Dianzani MU, Slater TF (eds) Free Radicals in Liver Injury. IRL Press, Oxford
Cheeseman KH, Albano EF, Tomasi A, Slater TF (1985) Biochemical studies on the metabolic activation of halogenated alkanes. Environ Health Perspect 64:85–101
Boll M, Weber LWD, Becker E, Stampfl A (2001a) Mechanism of carbon tetrachloride-induced hepatotoxicity. Hepatocellular damage by reactive carbon tetrachloride metabolites. Z Naturforsch C. J Biosci 56(7-8):649–659
Ozaki M, Masuda Y (1993) Carbon tetrachloride-induced cell death in perfused livers from phenobarbital-pretreated rats under hypoxic conditions and various ionic milieu. Further evidence for calcium-dependent irreversible changes. Biochem Pharmacol 46:2039–2049
Liu SL, Degli Esposti S, Yao T, Diehl AM, Zern MA (1995) Vitamin E therapy of acute CCl 4 -induced hepatic injury in mice is associated with inhibition of nuclear factor Kappa B binding. Hepatology 22:1474–1481
Czaja MJ, Xu J, Alt E (1995) Prevention of carbon tetrachloride-induced rat liver injury by soluble tumor necrosis factor receptor. Gastroenterol 108:1849–1854
Kull FC, Cuatrecasas P (1981) Possible measurements of internalization in the mechanism of in vitro cytotoxicity of tumor necrosis serum. Cancer Res 41:4885–4890
Boll M, Weber LWD, Becker E, Stampfl A (2001b) Pathogenesis of carbon tetrachloride-induced hepatocyte injury. Bioactivation of CCl 4 by cytochrome P450 and effects on lipid homeostasis. Z Naturforsch 56c:111–121
Boll M, Weber LWD, Becker E, Stampfl A (2001c) Hepatocyte damage induced by carbon tetrachloride. Inhibited lipoprotein secretion and altered lipoprotein composition. Z Naturforsch 56c:283–290
Ai G, Liu Q, Hua W, Huang Z, Wang D (2013) Hepatoprotective evaluation of the total flavonoids extracted from flowers of Abelmoschus manihot (L) Medic: In vivo and in vivo studies. J Ethnopharmacol 146:794–802
Arbab AH, Parvez MK, Al-Dosari MS, Al-Rehaily AJ, Al-Sohaibani M, Zaroug EE, Alsaid MS, Rafatullah S (2015) Hepatoprotective and antiviral efficacy of Acacia mellifera leaves fractions against Hepatitis B virus. Biomed Res Int. https://doi.org/10.1155/2015/929131
Singh R, Rao HS (2008) Hepatoprotective effect of the pulp/seed of Aegle marmelos correa ex Roxb against carbon tetrachloride induced liver damage in rats. Inter J Green Pharm:232–234
Rathee D, Kamboj A, Sidhu S (2018) Augmentation of hepatoprotective potential of Aegle marmelos in combination with piperine in carbon tetrachloride model in wistar rats. Chem Cent J 12:94. https://doi.org/10.1186/s/3065-018-0463-9
Dhruve P, Nauman M, Kale KR, Singh RP (2020) A novel hepatoprotective activity of Alangium salviifolium in mouse model. Drug Chem Toxicol. https://doi.org/10.1080/01480545.2020.1733593
Gargoum HM, Muftah SS, Shalmani SA, Mohammed HA, Alzoki AN, Debani AH, Fituri OA, Shari FE, Barassi IE, Meghil SE, Abdellatif AW (2013) Phytochemical screening and investigation of the effect of Alhagi maurorum (camel thorn) on carbon tetrachloride, acetaminophen and Adriamycin induced toxicity in experimental animals. J Sci Innov Res 2(6):1026–1033
Salah IA, Adnan JA, Abdulmalik MA, Maged SA (2008) Evaluation of hepatoprotective effect of Ephedra foliate, Alhagi maurorum, Capsella bursa-pastoris and Hisbiscus sabdariffa against experimentally induced liver injury in rats. Nat Prod Sci 14(2):95–98
Naji KM, Al-Shaibani ES, Alhadi FA, Al-Soudi SA, D’souza MR (2017) Hepatoprotective and antioxidant effects of single clove garlic against CCl4-induced hepatic damage in rabbits. BMC Complement Altern Med 17:411. https://doi.org/10.1186/s12906-017-1916-8
Zeashan H, Amresh G, Singh S, Rao CV (2008) Hepatoxicity activity of Amaranthus spinosus in experimental animals. Food Chem Toxicol 46:3417–3421
Jain S, Dixit VK, Malviya N, Ambawatia V (2009) Antioxidant and hepatoprotective activity of ethanol and aqueous extracts of Amorphophallus cmpanulatus Roxb. tubers. Acta Pol Pharm Drug Res 66(4):423–428
Sourabie TS, Ouedraogo N, Sawadogo WR, Yougbare N, Nikiema JB, Guissou IP, Nacoulma OG (2012) Evaluation of the anti-iceterus effect of crude powdered leaf of Argemone Mexicana L. (Papaveraceae) against CCl4-induced liver injury in rats. IJPSR 3(10):491–496
Wang J-H, Choi M-K, Shin J-W, Hwang S-Y, Son C-G (2012) Antifibrotic effects of Artemisia capillaris and Artemisia iwayomagi in a carbon tetrachloride-induced chronic hepatic fibrosis animal model. J Ethnopharmacol 140:179–185
Surenda HB, Apana R (2007) Hepatoprotective properties of Bauhinia variegate bark extract. Yakugaku Zasshi 127(9):1503–1507
Gilani AH, Janbaz KH, Shah BH (1998) Esculetin prevents liver damage induced by paracetamol and CCl4. Pharm Res 37(1):31–35
Enas JK (2014) Phytochemicals investigation and hepato-protective studies of Iraqi Bryonia (Family Cucubitaceae). IJPSR 6(4):187–190
Akindele AL, Ezenwanebe KO, Anunobi CC, Adeyemi OO (2010) Hepatoprotective and in vivo antioxidant effects of Byrscocarpus coCClneus Schum. and Thonn (Connaraceae). J Ethnopharmacol 129:40–52
Singh S, Mehta A, Mehta P (2011) Hepatoprotective activity of Cajanus cajan against carbon tetrachloride induced liver damage. IJPSR 3(sup 2):146–147
Lodhi G, Singh HK, Pant KK, Hussain Z (2009) Hepatoprotective effects of Calotropis gigantean extract against carbon tetrachloride induced liver injury in rats. Acta Pharm 59:89–96
Josi YM, Kadam VJ, Patil YV, Kaldhone PR (2009) Investigation of hepatoprotective activity of aerial parts of Canna indica L. on carbon tetrachloride treated rats. J Pharm Res 2(12):1879–1882
Nasrin A, Iran R, Amir M (2007) Hepatoprotective activity of Capparis spinosa root bark against CCl4 induced hepatic damage in mice. Iranian J Pharm Res 6(4):285–290
Sahreen S, Khan MR, Khan RA (2011) Hepatoprotective effects of methanol extract of Carissa opaca leaves on CCl4-induced damage in rat. BMC Complement Altern Med 11:48 www.biomedcentral.com/1472-6882/11/48
Zang Y, Guo J, Dong H, Zhao X, Zhou L, Li X, Liu J, Niu Y (2011) Hydroxysafflor yellow A protects against chronic carbon tetrachloride-induced liver fibrosis. Eur J Pharmacol 660(2-3):438–444
Wu S, Yue Y, Tian H, Li Z, Li X, He W, Ding H (2013) Carthamus red from Carthamus tinctorius L. exerts antioxidant and hepatoprotective effect against CCl4-induced liver damage in rats via the NrF2 pathway. J Ethnopharmacol. https://doi.org/10.1016/j.jep.2013.04.054
Samojlik L, Lakic N, Mimica-Dukic N, Dakovic-Svajcer K, Bozin B (2010) Antioxidant and hepatoprotective potential of essential oils of (Coriandrum sativum L) and caraway (Carvum carvi L.) (Apiaceae). J Agric Food Chem 58:8848–8853
Shanmugasundaran R, Devi VK, Tresina PS, Maruthupandian A, Mohan VR (2010) Hepatoprotective activity of ethanol extracts of Clitoria ternatea L. and Cassia angustifolia vahl leaf against CCl4 induced liver toxicity in rats. IJRP 1(1):201–205
Ilavarasan R, Mohideen S, Vijayalakshmi M, Manonmani G (2001) Hepatoprotective effect of Cassia angustofolia Vahl. Indian J Pharm Sci 63(6):504–507
Pradeep K, Mohan CVR, Anand KG, Karthikeyan S (2005) Effect of pretreatment of Cassia fistula Linn. leaf extract against subacute CCl4 induced hepatotoxicity in rats. Indian J Exp Biol 43:526–530
Ahmed B, Khan S, Masood HM, Siddique AH (2008) Anti-hepatotoxic activity of Cichotyboside, a sequiterpene glycoside from seeds of Cichorium intybus. J Asian Nat Prod Res 10(3):218–223
Sadeghi H, Reza NM, Izadpanah G, Sohailla S (2008) Hepatoprotective effect of Cichorium intybus on CCl4-induced liver damage in rats. Afr J Biochem Res 2(6):141–144
Moselhy SS, Ali HKH (2009) Hepatoprotective effect of Cinnamon extracts against carbon tetrachloride induced oxidative stress and liver injury in rats. Boil Res 42:93–98
Bellassoued K, Hamed H, El Feki A, Ghrab F, Kallel R, van Pelt J, Lahyani A, Ayadi FM (2019) Protective effect of essential oil of Cinnamomum verum bark on hepatic and renal toxicity induced by carbon tetrachloride in rats. Appl Physiol Nutr Metab 44(6):606–618
Eidi A, Mortazvi P, Bazargan M, Zaringhalam J (2012) Hepatoprotective activity of Cinnamon ethanolic extract against CCl4-induced liver injury in rats. EXCU J 11:495–507
Karaca M, Iihan F, Altan H, Him A, Tutuncu M, Ozbek H (2005) Evaluation of hepatoprotective activity of Bergamot orange in rats. Eastern J Med 10:1–4
Bhavsar SK, Joshi P, Shah MB, Santani DD (2007) Investigation of hepatoprotective property of Citrus limon. Pharm Biol 45(4):303–311
Molehin OR, Oloyede OL, Idowu KA, Adeyanju AA, Olowoyeye AO, Tubi OI, Komolafe OE, Gold AS (2017) White butterfly (Clerodendrum volubile) leaf extract protect against carbon tetrachloride-induced hepatotoxicity in rats. Biomed Pharmacother 96:924–929
Pandey A, Bigoniya P, Raj V, Patel KK (2011) Pharmacological Screening of Coriandrum sativum Linn. for hepatoprotective activity. J Pharm Bio allied Sci 3(3):435–441
Sreelatha S, Padma PR, Umadevi M (2009) Protective effects of Coriandrum sativum extracts on carbon tetrachloride-induced hepatotoxicity in rats. Food Chem Toxicol 47:702–708
Li L, Zhou Y-F, Li Y-L, Wang L-L, Arai H, Xu Y (2017) In vitro and in vivo antioxidative and hepatoprotective activity of aqueous extract of Cortex dictamni. World J Gastroentrol 23(16):2912–2927
Lee G-H, Lee H-Y, Choi M-K, Chung M-K, Kim S-W (2017) Protective effect of Curcuma longa L. extract on CCl4-induced acute hepatic stress. BMC Res Notes:10:77. https://doi.org/10.1186/s13104-017-2409-z
Raja S, Nazeer Ahamed KFH, Kumar V, Mukherjee K, Bandyopadhyay A, Mukherjee PK (2007) Antioxidant effect of Cytisus scoparius against carbon tetrachloride treated liver injury in rats. J Ethnopharmacol 109:41–47
Balogun FO, Ashafa AOT (2016) Antioxidant and hepatoprotective activities of Dicoma anomala Sond. aqueous root extract against carbon tetrachloride-induced liver damage in Wistar rats. J Tradit Clin Med 36(4):504–513
Yeh Y-H, Hsieh Y-L, Lee Y-T (2013) Effects of yam peel extract against carbon tetrachloride-induced hepatotoxicity in rats. J Agric Food Chem 61:7387–7396
Beedimani RS, Shetkar S (2015) Hepatoprotective activity of Eclipta alba against carbon tetrachloride-induced hepatotoxicity in albino rats. Inter J Basic Clin Pharm 4(3):404–409
Sultana S, Ahmad S, Khan N, Jahangir T (2005) Effect of Emblica officinalis (Gaertn) on CCl4 induced hepatic toxicity and DNA synthesis in Wistar rats. Indian J Exp Biol 43:430–436
Gupta G, More AS, Kumari RR, Lingaraju MC, Kumar D, Kumar D, Mishra SK, Tandan SK (2014) Protective effect of alcoholic extract of Entada pursaetha DC. against CCL4 induced hepatotoxicity in rats. Indian J Exp Biol 52:207–214
Pareek GA, Issarani R, Nagori BP (2013) Antioxidant hepatoprotective activity of Fagonia schweinfurthii (Hadidi) Hadidi extract in carbon tetrachloride induced hepatotoxicity in HepG2 cell line and rats. J Ethnopharmacol 150:973–981
Sharma M, Abid R, Ahmad Y, Nabi NG (2017) Protective effect of leaves of Fiscus carica against carbon tetrachloride-induced hepatic damage in rats. UK J Pharm Biosci 5(1):6–11
Hsieh PC, Ho YL, Huang GJ, Huang MH, Chiang YC, Huang SS, Hou WC, Chang YS (2011) Hepatoprotective effect of the aqueous extract of Flemingia macrophylla on carbon tetrachloride-induced acute hepatotoxicity in rats through anti-oxidant activities. Am J Chin Med 39(2):349–365
Khattab HAH (2012) Effect of Ginkgo biloba leaves aqueous extract on carbon tetrachloride induced acute hepatotoxicity in rats. Egypt J Hosp Med 48:483–495
Nwidu LL, Oboma YI, Elmorsy E, Carter WG (2018) Alleviation of carbon tetrachloride-induced hepatocellular damage and oxidative stress with a leaf extract of Glyphae brevis (Tiliaceae). J Basic Clin Physiol Pharmacol 29(6):609–619
Duh P-D, Lin S-L, Wu S-C (2011) Hepatoprotection of Graptopetalum paraguayense E. Walther on CCl4-induced liver damage and inflammation. J Ethnopharmacol 134:379–385
Zhang W, Zhang X, Xie J, Zhao S, Liu J, Liu H, Wang J, Wang Y (2017) Seabuckthorn berry pollysacharide protects against carbon tetrachloride-induced hepatotoxicity in mice via anti-oxidative and anti-inflammatory activities. Food Funct. https://doi.org/10.1039/C7FO00399D
Shahjahan M, Vani G, Shyamala Devi CS (2005) Protective effect of Idigofolia oblongifolia in CCl4- induced hepatotoxicity. J Med Food 8(2):261–265
Khan RA, Khan MR, Ahmed M, Sahreen S, Shah AN, Shah MS, Bokhari J, Rashid U, Ahmed B, Jan S (2012) Hepatoprotection with a chloroform extract of Launea procumbens against CCl4-induced injuries in rats. BMS Compl Altern Med 12:114 http://www.biomedcentral.com/1472-6882/12/114
Mohamed MA, Eldin IMT, Mohammed AH, Hassan HM (2016) Effects of Lawsonia inermis L. (Henna) leaves’ methanolic extact on carbon tetrachloride-induced hepatotoxicity in rats. J Intercult Ethnopharmacol 5(1):22–26. https://doi.org/10.5455/jice.20151123043218
Hossain CM, Maji HS, Chakraborty P (2011) Hepatoprotective activity of Lawsonia inermis Linn, warm aqueous extract in carbon tetrachloride induced hepatic injury in Wistar rats. Asian J Pharm Clin Res 4(3):106–109
Sailar GU, Dudhrejiya AV, Seth AK, Maheshwari R, Shah N, Aundhia C (2010) Hepatoprotective effect of Leucas cephalotes spreng on CCl4 induced liver damage in rats. Pharmacology Online 1:30–38
Ulaganathan I, Divya D, Radha K, Vijayakumar TM, Dhanaraju MD (2010) Protective effect of Luffa acurangula (Var) amara against carbon tetrachloride-induced hepatotoxicity in experimental rats. Res J Biol Sci 5(9):615–624
Wills PJ, Asha VV (2006) Protective effect of Lygodium flexuosum (L.) Sw. extract against carbon tetrachloride-induced acute liver injury in rats. J Ethnopharmacol 108:320–326
Chaudhary A, Bhandari A, Pandurangan A (2011) Hepatic activity of methanolic extract of Madhuca indica on carbon tetrachloride- induced hepatotoxicity in rats. Pharmacology Online 1:873–880
Patel PK, Sahu J, Prajapati NK, Dubey BK, Alia A (2012) Hepatoprotective effect of ethanolic and hydro alcoholic leaf extract of Madhuca indica in carbon tetrachloride intoxicated rat. Res J Pharmacol Pharmacodynamics 4(5):311–314
Ramakrishna S, Geetha KM, Bhaskargopal PVVS, Ranjit Kumar P, Charan Madav P, Umachandar L (2011) Effect of Mallotus philippensis Muell-Arg leaves against hepatotoxicity of carbon tetrachloride in rats. IJPSR 2(2):74–83
Pramod K, Deval RG, Lakshmayya RSS (2008) Antioxidant and hepatoprotective activity of tubers of Momordica tuberosa Cogn. against CCl4 induced liver injury in rats. Indian J Exp Biol 46:510–513
Bellassoued K, Hsouna AB, Athmouni K, Pelt J, Ayadi FM, Rebai T, Elfeki A (2018) Protective effects of Mentha piperita L. leaf essential oil against CCl4 induced hepatic oxidative damage and renal failure in rats. Lipids Health Dis 17:9. https://doi.org/10.1186/s12944-017-064S-9
Patil K, Mall A (2012) Hepatoprotective activity of Mentha arvensis Linn. leaves against CCl4 induced liver damage in rats. Asian Pac J Trop Dis 2(1):S223–s226
Rajendran R, Hemalatha S, Akasalai K, Madhakrishna CH, Vittal BS, Sundaram RM (2009) Hepatoprotective activity of Mimosa pudica leaves against carbon tetrachloride induced toxicity. J Nat Prod 2:116–122
Purkayastha A, Chakravarty P, Dewan B (2016) Evaluation of hepatoprotective activity of the ethanolic extract of leaves of Mimosa pudica Linn.in carbon tetrachloride induced hepatic injury in albino rats. Inter J Basic Clin Pharmacol 5(2):496–501
Jain A, Soni M, Deb L, Jain A, Rout SP, Gupta VB, Krishna KL (2008) Antioxidant and hepatoprotective activity of ethanolic and aqueous extracts of Momordica dioica Roxb. leaves. J Ethnopharmacol 115:61–66
Singhal KG, Gupta GD (2012) Hepatoprotective and antioxidant activity of methanolic extract of flowers of Nerum oleander against CCl4-induced liver injury in rats. Asian Pac J Trop Med 5(9):677–683
Abdus SS, Rahmat AK, Mushtaq A, Nawshad M (2016) Hepatoprotective role of Nicotiana plumbaginifolia Linn. against carbon tetrachloride-induced injuries. Toxicol Ind Health 32(2):292–298. https://doi.org/10.1177/0748233713498448
Ustuner D, Colak E, Dincer M, Tekin N, Donmez DB, Akyuz F, Colak E, Kolac UK, Entok E, Ustuner MC (2018) Post treatment effects of Olea europaea L. leaf extract on carbon tetrachloride-induced liver injury and oxidative stress in rats. J Med Food 00(0):1–6
Sikander M, Malok S, Parveen K, Ahmad M, Yadav D, Hafeez ZB, Bansal M (2013) Hepatoprotective effect of Origanum vulgare in Wistar rats against carbon tetrachloride-induced hepatotoxicity. Protoplasma 250:483–493
Brai BIC, Adisa RA, Odetola AA (2014) Hepatoprotective properties of aqueous leaf extract of Persea Americana, Mill (Lauraceae) ‘avocado’ against CCl4-induced damage in rats. Afr J Tradit Complement Altern Med 11(2):237–244
Ezzat MI, Okba MM, Ahmed SH, El-Banna AP, Mohamed SO, Ezzat SM (2020) In-dept hepatoprotective mechanisistic study of Phyllanthus niruri: in vitro and in vivo studies and its chemical characterization. PLoS One 15(1):e0226185. https://doi.org/10.1371/journal.pone.0226185
Khalaf-Allah AM, El-Gengahi SE, Hamed MA, Zahran HG, Mohammed MA (2016) Chemical composition of golden berry leaves against hepato-renal fibrosis. J Diet Suppl 13(4):378–392
Abdel Raoof GF, Said AA, Mohamed KY, Gomaa HA (2020) Phytoconstituents and bioactivities of the bark of Pleiogynium timorense (DC) Leenh (Anacardiaceae). J Herbmed Pharmacol 9(1):20–27
Jayakumar T, Ramesh E, Geraldine P (2006) Antioxidant activity of the oyster mushroom, Pleurotus ostreatus, on CCl4-induced liver injury in rats. Food Chem Toxicol 44:1989–1996
Mahmud ZA, Bachor SC, Qais N (2012) Antioxidant and hepatoprotective activities of ethanolic extracts of leaves of Preruna esculenta Roxb against carbon tetrachloride-induced liver damage in rats. J Young Pharm 4(4). https://doi.org/10.4103/0975-1483-104360
Syed SN, Rizvi W, Kumar A, Khan AA, Moin S, Ahsan A (2014) In vitro antioxidant and in vivo hepatoprotective activity of leave extract of Raphanus sativus in rats using CCl4 model. Afr J Tradit Complement Altern Med 11(3):102–106
Kalegari M, Gemin CAB, Araujo-silva N, de Brito NJ, Lopez JA, Tozetto S, Almeida M, Migue IMD, Stien D, Miguel OG (2014) Chemical composition, antioxidant activity and hepatoprotective potential of Rourea induta planch (Connaraceae) against CCl4-induced liver injury in female rats. Nutr 30:713–718
Rao GMM, Rao CV, Pushpangadan P, Shirwaikar A (2006) Hepatoprotective effects of rubiadin, a major constituent of Rubia cordifolia Linn. J Ethnopharmacol 103:484–490
Tukaappo NK, Londonkar RL, Nayaka HB, Kumar SCB (2015) Cytotoxicity and hepatoprotective attributes of methanolic extract of Rumex vesicarius L. Biol Res 48(19). https://doi.org/10.1186/s40659-015-0009-B
Sun ZL, Gao GL, Xia YF, Qiao ZY (2011) A new hepatoprotective saponin from Semen celosia cristatate. Fitoterapia 82(4):591–594
Shahjahan M, Sabitha KE, Jainu M, Shyamala Devi CS (2004) Effect of Solanum trilobatum against carbon tetrachloride induced hepatic damage in albino rats. Indian J Med Res 120:194–198
Gupta RK, Hussain T, Panigrahi G, Das A, Singh GN, Sweety K, Faiyazuddin MD, Rao CV (2011) Hepatoprotective effect of Solanum xanthocarpum fruit extract against CCl4-induced acute liver toxicity in experimentals. Asian Pac J Trop Med 4(12):964–968
Nwidu LL, Elmorsy E, Oboma YI, Carter WG (2018) Hepatoprotective and antioxidant activities of Spondias mombin leaf and stem extracts against carbon tetrachloride-induced hepatotoxicity. J Taibah Univ Med Sci 13(3):262–271
Kokhdan EP, Ahmadi K, Sadeghi H, Dadgary F, Danaei N, Aghamaali MR (2017) Hepatoprotective effect of Stachys pilifera ethanol extract in carbon tetrachloride-induced hepatotoxicity in rats. Pharm Biol 55(1):1389–1393
Deng J-S, Chang Y-S, Wen C-L, Liao J-C, Hou W-C, Amagaya S, Huang S-S, Huang G-J (2012) Hepatoprotective effect of the ethanol extract of Vitis thunbergii on carbon tetrachloride-induced acute hepatotoxicity in rats through anti-oxidative activities. J Ethnopharmacol 142:795–803
Song A, Ko HJ, Lai MN, Ng LT (2011) Protective effects of Wu-Liang-Shen (Xylaria nigtipes) on carbon tetrachloride-induced hepatotoxicity in mice. Immunopharmacol Immunotoxicol 33(3):453–460
Oke GO, Abiodun AA, Imafidon CE (2019) Zingiber officinale (Roscoe) mitigates CCl4-induced liver histology and biochemical derangements through antioxidant, membrane-stabilizing and tissue-regenerating potential. Toxicol Rep 6:416–425
Shen X, Tang Y, Yang R, Yu L, Fang T, Duan J (2009) The protective effect of Zizyphus jujube fruit on carbon tetrachloride-induced hepatic injury in mice by anti-oxidative activities. J Ethnopharmacol 122:555–560
Chang L, Xu D, Zhu J, Ge G, Kong X, Zhou Y (2020) Herbal therapy for the treatment of acetaminophen-associated liver injury: recent advances and future perspectives. Front Pharmacol 11:313. https://doi.org/10.3389/fphar.2020.00313
Stickel F, Shouval D (2015) Hepatotoxicity of herbal and dietary supplements: an update. Arch Toxicol 89(6):851–865
Janghel V, Patel P, Chandel SS (2019) Plants used for the treatment of icterus (jaundice) in Central India: A review. Ann Hepatol 18:658–672
Zhu J, Chen M, Borlak J (2019) The landscape of hepatobiliary adverse reactions across 53 herbal and dietary supplements reveals immune-mediated injury as a common cause of hepatitis. Arch Toxicol 94(1):273–279
Shakya AK (2020) Drug-induced hepatotoxicity and hepatoprotective medicinal plants: a review. Indian J Pharm Edu Res 54(2):234–247
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Ugwu, C.E., Suru, S.M. Medicinal plants with hepatoprotective potentials against carbon tetrachloride-induced toxicity: a review. Egypt Liver Journal 11, 88 (2021). https://doi.org/10.1186/s43066-021-00161-0
- Carbon tetrachloride
- Medicinal plants
- Folkloric medicine