Generic placeholder image

Current Molecular Medicine


ISSN (Print): 1566-5240
ISSN (Online): 1875-5666

Review Article

Deciphering Molecular Mechanisms of Carbon Tetrachloride- Induced Hepatotoxicity: A Brief Systematic Review

Author(s): Muhammad Mazhar Fareed, Hina Khalid, Sana Khalid and Sergey Shityakov*

Volume 24, Issue 9, 2024

Published on: 05 October, 2023

Page: [1124 - 1134] Pages: 11

DOI: 10.2174/0115665240257603230919103539

Price: $65


The liver plays a critical role in metabolic processes, making it vulnerable to injury. Researchers often study carbon tetrachloride (CCl4)-induced hepatotoxicity in model organisms because it closely resembles human liver damage. This toxicity occurs due to the activation of various cytochromes, including CYP2E1, CYP2B1, CYP2B2, and possibly CYP3A, which produce the trichloromethyl radical (CCl3*). CCl3* can attach to biological molecules such as lipids, proteins, and nucleic acids, impairing lipid metabolism and leading to fatty degeneration. It can also combine with DNA to initiate hepatic carcinogenesis. When exposed to oxygen, CCl3* generates more reactive CCl3OO*, which leads to lipid peroxidation and membrane damage. At the molecular level, CCl4 induces the release of several inflammatory cytokines, including TNF-α and NO, which can either help or harm hepatotoxicity through cellular apoptosis. TGF-β contributes to fibrogenesis, while IL-6 and IL-10 aid in recovery by minimizing anti-apoptotic activity and directing cells toward regeneration. To prevent liver damage, different interventions can be employed, such as antioxidants, mitogenic agents, and the maintenance of calcium sequestration. Drugs that prevent CCl4- induced cytotoxicity and proliferation or enhance CYP450 activity may offer a protective response against hepatic carcinoma.

Keywords: Carbon tetrachloride, liver, hepatotoxicity, cytochromes, inflammation, oxidative stress.

Ihedioha TE, et al. Hepatoprotective and antioxidant activities of Pterocarpus santalinoides methanol leaf extract. Afr J Pharm Pharmacol 2019; 13(18): 359-73.
Yi R. Antioxidant capacity-related preventive effects of Shoumei (slightly fermented Camellia sinensis) polyphenols against hepatic injury. Oxid Med Cell Longev 2020; 2020: 9329356.
Mohi-ud-din R, Mir RH, Sawhney G, Dar MA, Bhat ZA. Possible pathways of hepatotoxicity caused by chemical agents. Curr Drug Metab 2019; 20(11): 867-79.
[] [PMID: 31702487]
Malhi H, Gores GJ. Cellular and molecular mechanisms of liver injury. Gastroenterology 2008; 134(6): 1641-54.
[] [PMID: 18471544]
Bibi Z. Retraction: Role of cytochrome P450 in drug interactions. Nutr Metab 2014; 11(1): 11.
[] [PMID: 24529076]
Shityakov S, Broscheit J, Puskás I, Roewer N, Foerster C. Three-dimensional quantitative structure-activity relationship and docking studies in a series of anthocyanin derivatives as cytochrome P450 3A4 inhibitors. Adv Appl Bioinform Chem 2014; 7: 11-21.
[] [PMID: 24741320]
Bibi Z. Role of cytochrome P450 in drug interactions. Nutr Metab 2008; 5(1): 27.
[] [PMID: 18928560]
Shityakov S, Förster C. Pharmacokinetic delivery and metabolizing rate of nicardipine incorporated in hydrophilic and hydrophobic cyclodextrins using two-compartment mathematical model. ScientificWorldJournal 2013; 2013: 1-9.
[] [PMID: 24391458]
Weber LWD, Boll M, Stampfl A. Hepatotoxicity and mechanism of action of haloalkanes: Carbon tetrachloride as a toxicological model. Crit Rev Toxicol 2003; 33(2): 105-36.
[] [PMID: 12708612]
Hosono-Fukao T, Hosono T, Seki T, Ariga T. Diallyl trisulfide protects rats from carbon tetrachloride-induced liver injury. J Nutr 2009; 139(12): 2252-6.
[] [PMID: 19812219]
Horst AK, Tiegs G, Diehl L. Contribution of macrophage efferocytosis to liver homeostasis and disease. Front Immunol 2019; 10: 2670.
[] [PMID: 31798592]
Balakrishnan BB, Krishnasamy K, Mayakrishnan V, Selvaraj A. Moringa concanensis Nimmo extracts ameliorates hyperglycemia-mediated oxidative stress and upregulates PPARγ and GLUT4 gene expression in liver and pancreas of streptozotocin-nicotinamide induced diabetic rats. Biomed Pharmacother 2019; 112: 108688.
[] [PMID: 30798121]
Manibusan MK, Odin M, Eastmond DA. Postulated carbon tetrachloride mode of action: A review. J Environ Sci Health Part C Environ Carcinog Ecotoxicol Rev 2007; 25(3): 185-209.
[] [PMID: 17763046]
Wong FWY, Chan WY, Lee SST. Resistance to carbon tetrachloride-induced hepatotoxicity in mice which lack CYP2E1 expression. Toxicol Appl Pharmacol 1998; 153(1): 109-18.
[] [PMID: 9875305]
Unsal V, Cicek M. Sabancilar İ. Toxicity of carbon tetrachloride, free radicals and role of antioxidants. Rev Environ Health 2021; 36(2): 279-95.
[] [PMID: 32970608]
Yadav U, Ramana KV. Regulation of NF-κB-induced inflammatory signaling by lipid peroxidation-derived aldehydes. Oxid Med Cell Longev 2013; 2013: 690545.
Fritz KS, Petersen DR. Exploring the biology of lipid peroxidation-derived protein carbonylation. Chem Res Toxicol 2011; 24(9): 1411-9.
[] [PMID: 21812433]
Hickman IJ, Jonsson JR, Prins JB, et al. Modest weight loss and physical activity in overweight patients with chronic liver disease results in sustained improvements in alanine aminotransferase, fasting insulin, and quality of life. Gut 2004; 53(3): 413-9.
[] [PMID: 14960526]
Hartley DP, Kolaja KL, Reichard J, Petersen DR. 4-Hydroxynonenal and malondialdehyde hepatic protein adducts in rats treated with carbon tetrachloride: Immunochemical detection and lobular localization. Toxicol Appl Pharmacol 1999; 161(1): 23-33.
[] [PMID: 10558920]
Beddowes EJ, Faux SP, Chipman JK. Chloroform, carbon tetrachloride and glutathione depletion induce secondary genotoxicity in liver cells via oxidative stress. Toxicology 2003; 187(2-3): 101-15.
[] [PMID: 12699900]
Berridge MJ. Elementary and global aspects of calcium signalling. J Exp Biol 1997; 200(2): 315-9.
[] [PMID: 9050239]
Moore L, Schoenberg DR, Long RM. Impact of halogenated compounds on calcium homeostasis in hepatocytes. Environ Health Perspect 1990; 84: 149-53.
[] [PMID: 2190809]
Hemmings SJ, Pulga VB, Tran ST, Uwiera RRE. Differential inhibitory effects of carbon tetrachloride on the hepatic plasma membrane, mitochondrial and endoplasmic reticular calcium transport systems: Implications to hepatotoxicity. Cell Biochem Funct 2002; 20(1): 47-59.
[] [PMID: 11835270]
Albano E, Carini R, Parola M, et al. Effects of carbon tetrachloride on calcium homeostasis. Biochem Pharmacol 1989; 38(16): 2719-25.
[] [PMID: 2764992]
Limaye PB, Apte UM, Shankar K, Bucci TJ, Warbritton A, Mehendale HM. Calpain released from dying hepatocytes mediates progression of acute liver injury induced by model hepatotoxicants. Toxicol Appl Pharmacol 2003; 191(3): 211-26.
[] [PMID: 13678654]
Schiffrin EL. Oxidative stress, nitric oxide synthase, and superoxide dismutase: A matter of imbalance underlies endothelial dysfunction in the human coronary circulation. Hypertension 2008; 51(1): 31-2.
Schulz E, Jansen T, Wenzel P, Daiber A, Münzel T. Nitric oxide, tetrahydrobiopterin, oxidative stress, and endothelial dysfunction in hypertension. Antioxid Redox Signal 2008; 10(6): 1115-26.
[] [PMID: 18321209]
Gracia-Sancho J, Laviña B, Rodríguez-Vilarrupla A, et al. Increased oxidative stress in cirrhotic rat livers: A potential mechanism contributing to reduced nitric oxide bioavailability. Hepatology 2008; 47(4): 1248-56.
[] [PMID: 18273863]
Muriel P. Nitric oxide protection of rat liver from lipid peroxidation, collagen accumulation, and liver damage induced by carbon tetrachloride. Biochem Pharmacol 1998; 56(6): 773-9.
[] [PMID: 9751083]
Tipoe GL, Leung TM, Liong E, et al. Inhibitors of inducible nitric oxide (NO) synthase are more effective than an NO donor in reducing carbon-tetrachloride induced acute liver injury. Histol Histopathol 2006; 21(11): 1157-65.
[PMID: 16874658]
Cai Y, Gong L, Qi X, Li X, Ren J. Apoptosis initiated by carbon tetrachloride in mitochondria of rat primary cultured hepatocytes. Acta Pharmacol Sin 2005; 26(8): 969-75.
[] [PMID: 16038630]
Guicciardi ME, Gores GJ. Apoptosis: A mechanism of acute and chronic liver injury. Gut 2005; 54(7): 1024-33.
[] [PMID: 15951554]
Aram G, Potter JJ, Liu X, Torbenson MS, Mezey E. Lack of inducible nitric oxide synthase leads to increased hepatic apoptosis and decreased fibrosis in mice after chronic carbon tetrachloride administration. Hepatology 2008; 47(6): 2051-8.
[] [PMID: 18506890]
Graupera M, García-Pagán JC, Abraldes JG, et al. Cyclooxygenase-derived products modulate the increased intrahepatic resistance of cirrhotic rat livers. Hepatology 2003; 37(1): 172-81.
[] [PMID: 12500202]
Theodorakis NG, Wang YN, Wu JM, Maluccio MA, Sitzmann JV, Skill NJ. Role of endothelial nitric oxide synthase in the development of portal hypertension in the carbon tetrachloride-induced liver fibrosis model. Am J Physiol Gastrointest Liver Physiol 2009; 297(4): G792-9.
[] [PMID: 19628654]
Wiest R, Groszmann RJ. The paradox of nitric oxide in cirrhosis and portal hypertension: Too much, not enough. Hepatology 2002; 35(2): 478-91.
[] [PMID: 11826425]
Van de Casteele M, van Pelt JF, Nevens F, Fevery J, Reichen J. Low NO bioavailability in CCl4 cirrhotic rat livers might result from low NO synthesis combined with decreased superoxide dismutase activity allowing superoxide-mediated NO breakdown: A comparison of two portal hypertensive rat models with healthy controls. Comp Hepatol 2003; 2(1): 2.
[] [PMID: 12575897]
Ferguson JW, Dover AR, Chia S, Cruden NL, Hayes PC, Newby DE. Inducible nitric oxide synthase activity contributes to the regulation of peripheral vascular tone in patients with cirrhosis and ascites. Gut 2006; 55(4): 542-6.
[] [PMID: 16299035]
Vallance P, Moncada S. Hyperdynamic circulation in cirrhosis: A role for nitric oxide? Lancet 1991; 337(8744): 776-8.
[] [PMID: 1706450]
Bhimani EK, Serracino-Inglott F, Sarela AI, Batten JJ, Mathie RT. Hepatic and mesenteric nitric oxide synthase expression in a rat model of CCl4-induced cirrhosis. J Surg Res 2003; 113(1): 172-8.
[] [PMID: 12943827]
Kwon SY, Groszmann RJ, Iwakiri Y. Increased neuronal nitric oxide synthase interaction with soluble guanylate cyclase contributes to the splanchnic arterial vasodilation in portal hypertensive rats. Hepatol Res 2007; 37(1): 58-67.
[] [PMID: 17300699]
Bataller R, Brenner DA. Liver fibrosis. J Clin Invest 2005; 115(2): 209-18.
[] [PMID: 15690074]
Zhang CY, Yuan WG, He P, Lei JH, Wang CX. Liver fibrosis and hepatic stellate cells: Etiology, pathological hallmarks and therapeutic targets. World J Gastroenterol 2016; 22(48): 10512-22.
[] [PMID: 28082803]
de Meijer VE, Sverdlov DY, Popov Y, et al. Broad-spectrum matrix metalloproteinase inhibition curbs inflammation and liver injury but aggravates experimental liver fibrosis in mice. PLoS One 2010; 5(6): e11256.
[] [PMID: 20593020]
Domitrović R, Jakovac H, Tomac J, Šain I. Liver fibrosis in mice induced by carbon tetrachloride and its reversion by luteolin. Toxicol Appl Pharmacol 2009; 241(3): 311-21.
[] [PMID: 19747501]
Iredale JP, Benyon RC, Pickering J, et al. Mechanisms of spontaneous resolution of rat liver fibrosis. Hepatic stellate cell apoptosis and reduced hepatic expression of metalloproteinase inhibitors. J Clin Invest 1998; 102(3): 538-49.
[] [PMID: 9691091]
Kisseleva T, Cong M, Paik Y, et al. Myofibroblasts revert to an inactive phenotype during regression of liver fibrosis. Proc Natl Acad Sci 2012; 109(24): 9448-53.
[] [PMID: 22566629]
Zeisberg M, Yang C, Martino M, et al. Fibroblasts derive from hepatocytes in liver fibrosis via epithelial to mesenchymal transition. J Biol Chem 2007; 282(32): 23337-47.
[] [PMID: 17562716]
Yoshiji H, Kuriyama S, Miyamoto Y, et al. Tissue inhibitor of metalloproteinases-1 promotes liver fibrosis development in a transgenic mouse model. Hepatology 2000; 32(6): 1248-54.
[] [PMID: 11093731]
Sun J, Wu Y, Long C, et al. Anthocyanins isolated from blueberry ameliorates CCl4 induced liver fibrosis by modulation of oxidative stress, inflammation and stellate cell activation in mice. Food Chem Toxicol 2018; 120: 491-9.
[] [PMID: 30056145]
Rivera CA, Bradford BU, Hunt KJ, et al. Attenuation of CCl 4 -induced hepatic fibrosis by GdCl 3 treatment or dietary glycine. Am J Physiol Gastrointest Liver Physiol 2001; 281(1): G200-7.
[] [PMID: 11408273]
Liu C, Tao Q, Sun M, et al. Kupffer cells are associated with apoptosis, inflammation and fibrotic effects in hepatic fibrosis in rats. Lab Invest 2010; 90(12): 1805-16.
[] [PMID: 20921949]
Schwabe RF, Brenner DA. Mechanisms of Liver Injury. I. TNF-α-induced liver injury: role of IKK, JNK, and ROS pathways. Am J Physiol Gastrointest Liver Physiol 2006; 290(4): G583-9.
[] [PMID: 16537970]
Bradham CA, Plümpe J, Manns MP, Brenner DA, Trautwein C. Mechanisms of hepatic toxicity. I. TNF-induced liver injury. Am J Physiol 1998; 275(3): G387-92.
[PMID: 9724248]
Simeonova PP, Gallucci RM, Hulderman T, et al. The role of tumor necrosis factor-α in liver toxicity, inflammation, and fibrosis induced by carbon tetrachloride. Toxicol Appl Pharmacol 2001; 177(2): 112-20.
[] [PMID: 11740910]
Son G, Iimuro Y, Seki E, Hirano T, Kaneda Y, Fujimoto J. Selective inactivation of NF-κB in the liver using NF-κB decoy suppresses CCl4 -induced liver injury and fibrosis. Am J Physiol Gastrointest Liver Physiol 2007; 293(3): G631-9.
[] [PMID: 17640975]
Fan C, Yang J, Engelhardt JF. Temporal pattern of NFκB activation influences apoptotic cell fate in a stimuli-dependent fashion. J Cell Sci 2002; 115(24): 4843-53.
[] [PMID: 12432072]
Lee N-K, Lee S-Y. Modulation of life and death by the tumor necrosis factor receptor-associated factors (TRAFs). J Biochem Mol Biol 2002; 35(1): 61-6.
[PMID: 16248971]
Aggarwal BB. Tumour necrosis factors receptor associated signalling molecules and their role in activation of apoptosis, JNK and NF-kappa B. Ann Rheum Dis 2000; 59(90001(S1)): 6i-16.
[] [PMID: 11053079]
Taniguchi M, Takeuchi T, Nakatsuka R, Watanabe T, Sato K. Molecular process in acute liver injury and regeneration induced by carbon tetrachloride. Life Sci 2004; 75(13): 1539-49.
[] [PMID: 15261760]
Salazar-Montes A, Ruiz-Corro L, Sandoval-Rodriguez A, Lopez-Reyes A, Armendariz-Borunda J. Increased DNA binding activity of NF- k B, STAT-3, SMAD3 and AP-1 in acutely damaged liver. World J Gastroenterol 2006; 12(37): 5995-6001.
[] [PMID: 17009398]
Kanzler S, Lohse AW, Keil A, et al. TGF-β1 in liver fibrosis: An inducible transgenic mouse model to study liver fibrogenesis. Am J Physiol 1999; 276(4): G1059-68.
[PMID: 10198351]
Gressner AM, Weiskirchen R, Breitkopf K, Dooley S. Roles of TGF-beta in hepatic fibrosis. Front Biosci 2002; 7(4): A812.
[] [PMID: 11897555]
Ciuclan L, Ehnert S, Ilkavets I, et al. TGF-β enhances alcohol dependent hepatocyte damage via down-regulation of alcohol dehydrogenase I. J Hepatol 2010; 52(3): 407-16.
[] [PMID: 20129692]
Khimji A, Shao R, Rockey DC. Divergent transforming growth factor-β signaling in hepatic stellate cells after liver injury: Functional effects on ECE-1 regulation. Am J Pathol 2008; 173(3): 716-27.
[] [PMID: 18753413]
Nakerakanti S, Trojanowska M. Suppl 1: The role of TGF-β receptors in fibrosis. Open Rheumatol J 2012; 6(1): 156-62.
[] [PMID: 22802914]
Tahashi Y, Matsuzaki K, Date M, et al. Differential regulation of TGF-β signal in hepatic stellate cells between acute and chronic rat liver injury. Hepatology 2002; 35(1): 49-61.
[] [PMID: 11786959]
Date M, Matsuzaki K, Matsushita M, Tahashi Y, Furukawa F, Inoue K. Modulation of transforming growth factor β function in hepatocytes and hepatic stellate cells in rat liver injury. Gut 2000; 46(5): 719-24.
[] [PMID: 10764719]
Tsuchiya S, Tsukamoto Y, Taira E, LaMarre J. Involvement of transforming growth factor-β in the expression of gicerin, a cell adhesion molecule, in the regeneration of hepatocytes. Int J Mol Med 2007; 19(3): 381-6.
[] [PMID: 17273784]
Horiguchi N, Lafdil F, Miller AM, et al. Dissociation between liver inflammation and hepatocellular damage induced by carbon tetrachloride in myeloid cell-specific signal transducer and activator of transcription 3 gene knockout mice. Hepatology 2010; 51(5): 1724-34.
[] [PMID: 20196117]
Kovalovich K, DeAngelis RA, Li W, Furth EE, Ciliberto G, Taub R. Increased toxin-induced liver injury and fibrosis in interleukin-6-deficient mice. Hepatology 2000; 31(1): 149-59.
[] [PMID: 10613740]
Bansal MB, Kovalovich K, Gupta R, et al. Interleukin-6 protects hepatocytes from CCl4-mediated necrosis and apoptosis in mice by reducing MMP-2 expression. J Hepatol 2005; 42(4): 548-56.
[] [PMID: 15763341]
Louis H, Van Laethem JL, Wu W, et al. Interleukin-10 controls neutrophilic infiltration, hepatocyte proliferation, and liver fibrosis induced by carbon tetrachloride in mice. Hepatology 1998; 28(6): 1607-15.
[] [PMID: 9828225]

Rights & Permissions Print Cite
© 2024 Bentham Science Publishers | Privacy Policy