Toxicity of carbon tetrachloride, free radicals and role of antioxidants

AbstractSeveral chemicals, including environmental toxicants and clinically useful drugs, cause severe cellular damage to different organs of our body through metabolic activation to highly reactive substances such as free radicals. Carbon tetrachloride is an organic compound of which chemical formula is CCl₄. CCl4 is strong toxic in the kidney, testicle, brain, heart, lung, other tissues, and particularly in the liver. CCl4 is a powerful hepatoxic, nephrotoxic and prooxidant agent which is widely used to induce hepatotoxicity in experimental animals and to create hepatocellular carcinoma, hepatic fibrosis/cirrhosis and liver injury, chemical hepatitis model, renal failure model, and nephrotoxicity model in recent years. The damage-causing mechanism of CCl4 in tissues can be explained as oxidative damage caused by lipid peroxidation which starts after the conversion of CCl4 to free radicals of highly toxic trichloromethyl radicals (•CCl₃) and trichloromethyl peroxyl radical (•CCl₃O2) via cytochrome P450 enzyme. Complete disruption of lipids (i.e., peroxidation) is the hallmark of oxidative damage. Free radicals are structures that contain one or more unpaired electrons in atomic or molecular orbitals. These toxic free radicals induce a chain reaction and lipid peroxidation in membrane-like structures rich in phospholipids, such as mitochondria and endoplasmic reticulum. CCl4-induced lipid peroxidation is the cause of oxidative stress, mitochondrial stress, endoplasmic reticulum stress. Free radicals trigger many biological processes, such as apoptosis, necrosis, ferroptosis and autophagy. Recent researches state that the way to reduce or eliminate these CCl4-induced negative effects is the antioxidants originated from natural sources. For normal physiological function, there must be a balance between free radicals and antioxidants. If this balance is in favor of free radicals, various pathological conditions occur. Free radicals play a role in various pathological conditions including Pulmonary disease, ischemia / reperfusion rheumatological diseases, autoimmune disorders, cardiovascular diseases, cancer, kidney diseases, hypertension, eye diseases, neurological disorders, diabetes and aging. Free radicals are antagonized by antioxidants and quenched. Antioxidants do not only remove free radicals, but they also have anti-inflammatory, anti-allergic, antithrombotic, antiviral, and anti-carcinogenic activities. Antioxidants contain high phenol compounds and antioxidants have relatively low side effects compared to synthetic drugs. The antioxidants investigated in CCI4 toxicity are usually antioxidants from plants and are promising because of their rich resources and low side effects. Data were investigated using PubMed, EBSCO, Embase, Web of Science, DOAJ, Scopus and Google Scholar, Carbon tetrachloride, carbon tetrachloride-induced toxicity, oxidative stress, and free radical keywords. This study aims to enlighten the damage-causing mechanism created by free radicals which are produced by CCl4 on tissues/cells and to discuss the role of antioxidants in the prevention of tissue/cell damage. In the future, Antioxidants can be used as a therapeutic strategy to strengthen effective treatment against substances with high toxicity such as CCl4 and increase the antioxidant capacity of cells.

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Sympathetic Nervous System Control of Carbon Tetrachloride-Induced Oxidative Stress in Liver throughα-Adrenergic Signaling

Oxidative Medicine and Cellular Longevity ◽

10.1155/2016/3190617 ◽

2016 ◽

Vol 2016 ◽

pp. 1-11 ◽

Cited By ~ 5

Author(s):

Jung-Chun Lin ◽

Yi-Jen Peng ◽

Shih-Yu Wang ◽

Mei-Ju Lai ◽

Ton-Ho Young ◽

...

Keyword(s):

Oxidative Stress ◽

Lipid Peroxidation ◽

Nervous System ◽

Carbon Tetrachloride ◽

Sympathetic Nervous System ◽

Nerve Fibers ◽

Adrenergic Signaling ◽

Adrenergic Antagonist ◽

Sympathetic Nervous

In addition to being the primary organ involved in redox cycling, the liver is one of the most highly innervated tissues in mammals. The interaction between hepatocytes and sympathetic, parasympathetic, and peptidergic nerve fibers through a variety of neurotransmitters and signaling pathways is recognized as being important in the regulation of hepatocyte function, liver regeneration, and hepatic fibrosis. However, less is known regarding the role of the sympathetic nervous system (SNS) in modulating the hepatic response to oxidative stress. Our aim was to investigate the role of the SNS in healthy and oxidatively stressed liver parenchyma. Mice treated with 6-hydroxydopamine hydrobromide were used to realize chemical sympathectomy. Carbon tetrachloride (CCl4) injection was used to induce oxidative liver injury. Sympathectomized animals were protected from CCl4induced hepatic lipid peroxidation-mediated cytotoxicity and genotoxicity as assessed by 4-hydroxy-2-nonenal levels, morphological features of cell damage, and DNA oxidative damage. Furthermore, sympathectomy modulated hepatic inflammatory response induced by CCl4-mediated lipid peroxidation. CCl4induced lipid peroxidation and hepatotoxicity were suppressed by administration of anα-adrenergic antagonist. We conclude that the SNS provides a permissive microenvironment for hepatic oxidative stress indicating the possibility that targeting the hepaticα-adrenergic signaling could be a viable strategy for improving outcomes in patients with acute hepatic injury.

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Curcumin Reduce Sodium Fluoride-Induced Oxidative Stress in Rat Brain

Biosciences Biotechnology Research Asia ◽

10.13005/bbra/2609 ◽

2018 ◽

Vol 15 (1) ◽

pp. 71-77 ◽

Cited By ~ 1

Author(s):

Nagapuri Kiran Kumar ◽

Mesram Nageshwar ◽

Karnati Pratap Reddy

Keyword(s):

Oxidative Stress ◽

Lipid Peroxidation ◽

Oxidative Damage ◽

Oral Administration ◽

Rat Brain ◽

Sodium Fluoride ◽

Oxidative Stress Markers ◽

Stress Markers ◽

The Brain

This study reports the ameliorative role of curcumin against sodium fluoride (NaF) induced oxidative stress in the brain of rats. The rats were divided into control, NaF (20 mg/kg), NaF+Curcumin (20mg/kg) and Curcumin (20mg/kg) groups respectively and treated at everyday interval for 60 consecutive days. Oxidative stress markers in the brain were measured at 60th day. NaF treatment significantly increased LPO content, but decreased the level of GSH and activities of SOD, GPx, and CAT the brain of rats in comparison to the control rats. Oral administration of curcumin to fluoride exposed rats significantly reversed the content of lipid peroxidation, as well as enhanced the level of GSH and SOD, GPx and CAT activities to normal compared to NaF exposed rats. Thus, curcumin showed the potential to prevent sodium fluoride induced oxidative damage in the brain of rats and curcumin may be useful agents against neurodegeneration in the brain.

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Mitochondrial, lysosomal and DNA damages induced by acrylamide attenuate by ellagic acid in human lymphocyte

PLoS ONE ◽

10.1371/journal.pone.0247776 ◽

2021 ◽

Vol 16 (2) ◽

pp. e0247776

Author(s):

Ahmad Salimi ◽

Elahe Baghal ◽

Hassan Ghobadi ◽

Niloufar Hashemidanesh ◽

Farzad Khodaparast ◽

...

Keyword(s):

Oxidative Stress ◽

Lipid Peroxidation ◽

Dna Damage ◽

Ellagic Acid ◽

Human Lymphocytes ◽

Health Concern ◽

Cytochrome P450 Enzyme ◽

Dna Damages ◽

Ros Formation

Acrylamide (AA), is an important contaminant formed during food processing under high temperature. Due to its potential neurotoxicity, reproductive toxicity, hepatotoxicity, immunotoxicity, genotoxicity and carcinogenicity effects, this food contaminant has been recognized as a human health concern. Previous studies showed that acrylamide-induced toxicity is associated with active metabolite of acrylamide by cytochrome P450 enzyme, oxidative stress, mitochondrial dysfunction and DNA damage. In the current study, we investigated the role of oxidative stress in acrylamide’s genotoxicity and therapeutic potential role of ellagic acid (EA) in human lymphocytes. Human lymphocytes were simultaneously treated with different concentrations of EA (10, 25 and 50 μM) and acrylamide (50 μM) for 4 h at 37°C. After 4 hours of incubation, the toxicity parameters such cytotoxicity, ROS formation, oxidized/reduced glutathione (GSH/GSSG) content, malondialdehyde (MDA) level, lysosomal membrane integrity, mitochondria membrane potential (ΔΨm) collapse and 8-hydroxy-2’-deoxyguanosine (8-OHdG) were analyzed using biochemical and flow cytometry evaluations. It has been found that acrylamide (50 μM) significantly increased cytotoxicity, ROS formation, GSH oxidation, lipid peroxidation, MMP collapse, lysosomal and DNA damage in human lymphocytes. On the other hand, cotreatment with EA (25 and 50 μM) inhibited AA-induced oxidative stress which subsequently led to decreasing of the cytotoxicity, GSH oxidation, lipid peroxidation, MMP collapse, lysosomal and DNA damage. Together, these results suggest that probably the co-exposure of EA with foods containing acrylamide could decrease mitochondrial, lysosomal and DNA damages, and oxidative stress induced by acrylamide in human body.

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Oxidative Stress and Cancer: Chemopreventive and Therapeutic Role of Triphala

Antioxidants ◽

10.3390/antiox9010072 ◽

2020 ◽

Vol 9 (1) ◽

pp. 72 ◽

Cited By ~ 5

Author(s):

Sahdeo Prasad ◽

Sanjay K. Srivastava

Keyword(s):

Oxidative Stress ◽

Lipid Peroxidation ◽

Free Radicals ◽

Signaling Pathways ◽

Multiple Cell ◽

Multiple Signaling ◽

Immense Potential ◽

Cell Signaling Pathways ◽

Radioprotective Agent

Oxidative stress, caused by the overproduction of free radicals, leads to the development of many chronic diseases including cancer. Free radicals are known to damage cellular biomolecules like lipids, proteins, and DNA that results in activation of multiple signaling pathways, growth factors, transcription factors, kinases, inflammatory and cell cycle regulatory molecules. Antioxidants, which are classified as exogenous and endogenous, are responsible for the removal of free radicals and consequently the reduction in oxidative stress-mediated diseases. Diet and medicinal herbs are the major source of antioxidants. Triphala, which is a traditional Ayurvedic formulation that has been used for centuries, has been shown to have immense potential to boost antioxidant activity. It scavenges free radicals, restores antioxidant enzymes and non-enzyme levels, and decreases lipid peroxidation. In addition, Triphala is revered as a chemopreventive, chemotherapeutic, immunomodulatory, and radioprotective agent. Accumulated evidence has revealed that Triphala modulates multiple cell signaling pathways including, ERK, MAPK, NF-κB, Akt, c-Myc, VEGFR, mTOR, tubulin, p53, cyclin D1, anti-apoptotic and pro-apoptotic proteins. The present review focuses on the comprehensive appraisal of Triphala in oxidative stress and cancer.

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New Markers of Oxidative Damage to Macromolecules

Journal of Medical Biochemistry ◽

10.2478/v10011-007-0049-x ◽

2008 ◽

Vol 27 (1) ◽

pp. 1-16 ◽

Cited By ~ 18

Author(s):

Emina Čolak

Keyword(s):

Oxidative Stress ◽

Lipid Peroxidation ◽

Free Radicals ◽

Oxidative Damage ◽

Protein Modification ◽

Lipid Hydroperoxide ◽

The Body ◽

Oxidative Modification ◽

Toxic Effects ◽

Specific Marker

New Markers of Oxidative Damage to Macromolecules The presence of free radicals in biological material has been discovered some 50 years ago. In physiological conditions, free radicals, in the first place the ones of oxygen and nitrogen, are continuously synthesized and involved in the regulation of a series of physiological processes. The excess of free radicals is efficiently eliminated from the body in order to prevent their toxic effects. Toxic effects of free radicals may be classified into three groups: a) change of intracellular redox potential, b) oxidative modification of lipids, proteins and DNA, and c) gene activation. Lipid peroxidation involving cell membranes, lipoproteins and other molecules leads to the production of primary high-reactive intermediaries (alkyl radicals, conjugated dienes, peroxy- and alkoxyl radicals and lipid hydroperoxide), whose further breakdown generates the secondary products of lipid peroxidation: short-chain evaporable hydrocarbons, aldehydes and final products of lipid peroxidation: isoprostanes, MDA, 4-hydroxy-2, 3-transnonenal and 4,5-dihydroxydecenal which are important mediators of atherosclerosis, coronary disease, acute myocardial infarction, rheumatoid arthritis, systemic sclerosis and lupus erythematodes. Oxidative modification of proteins is manifested by changes in their primary, secondary and tertiary structures. Proteins have a specific biological function, and therefore their modification results in unique functional consequences. The nature of protein modification may provide valid information on the type of oxidants causing the damage. Chlorotyrosyl is a specific marker of oxidative damage to tyrosine caused by HOCl action, which most commonly reflects the involvement of neutrophils and monocytes in oxidative stress, while nitrotyrosyl indicates the presence of higher peroxy-nitrite synthesis. Methyonin and cysteine are the amino acids most sensitive to oxidative stress, carbonyl groups are markers of severe damage caused by free radicals, and di-tyrosyl is the most significant and sensitive marker of oxidative modification made by γ rays. >Carbonyl stress< is an important form of the secondary oxidation of proteins, where reducing sugars non-enzymatically react with amino groups of proteins and lipids and give rise to the production of covalent compounds known as advanced glycosylated end products (AGE-products). A hydroxyl radical damages the DNA, leading to a loss of base and the formation of abasic sites (AP sites), break of DNA chain and sugar modification. Final lipid peroxidation products (MDA) may covalently bind to DNA, producing the >DNA radicals< which are responsible for mutations. Measurement of an adequate oxidative stress biomarker may not only point to an early onset of disease, its progression and assessment of therapy effectiveness, but can also help in the clarification of the pathophysiological mechanisms of tissue damage caused by oxidative stress, prediction of disease prognosis and choice of appropriate treatment in the early stages of disease.

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Hepatoprotective role of Solenostemma argel growing in Egypt on ethanol induced oxidative damage in rats

Turkish Journal of Biochemistry ◽

10.1515/tjb-2016-0211 ◽

2017 ◽

Vol 42 (4) ◽

Author(s):

Mahgoub Mohamed Ahmed

Keyword(s):

Oxidative Stress ◽

Lipid Peroxidation ◽

Oxidative Damage ◽

Protective Effect ◽

Rat Liver ◽

Adult Male ◽

Total Protein ◽

Albino Rats ◽

Serum Total Protein

AbstractObjective:The objective of the current study is to investigate the protective effect ofMethods:Forty adult male albino rats were divided into four groups as control,Results:The results showed that, administration of EtOH caused a significant decrease (p<0.05) in serum total protein and albumin, whereas ALT and AST and lipid peroxidation (LPO) were increased following EtOH treatment.Conclusion:had a hepatoprotective role against EtOH-induce oxidative stress and inflammation in rat liver.

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Changes in lipid peroxidation during pregnancy and after delivery in rats: effect of pinealectomy

Reproduction ◽

10.1530/reprod/119.1.143 ◽

2000 ◽

pp. 143-149 ◽

Cited By ~ 9

Author(s):

RM Sainz ◽

RJ Reiter ◽

JC Mayo ◽

J Cabrera ◽

DX Tan ◽

...

Keyword(s):

Oxidative Stress ◽

Lipid Peroxidation ◽

Oxidative Damage ◽

Energy Demand ◽

Physiological State ◽

High Energy ◽

Free Radical Scavengers ◽

Radical Scavengers ◽

Oxygen Requirement ◽

Pregnant Rats

Pregnancy is a physiological state accompanied by a high energy demand of many bodily functions and an increased oxygen requirement. Because of the increased intake and utilization of oxygen, increased levels of oxidative stress would be expected. In the present study, the degree of lipid peroxidation was examined in different tissues from non-pregnant and pregnant rats after the delivery of their young. Melatonin and other indole metabolites are known to be direct free radical scavengers and indirect antioxidants. Thus the effect of pinealectomy at 1 month before pregnancy on the accumulation of lipid damage was investigated in non-pregnant and pregnant rats after the delivery of their young. Malonaldehyde and 4-hydroxyalkenal concentrations were measured in the lung, uterus, liver, brain, kidney, thymus and spleen from intact and pinealectomized pregnant rats soon after birth of their young and at 14 and 21 days after delivery. The same parameters were also evaluated in intact and pinealectomized non-pregnant rats. Shortly after delivery, lipid oxidative damage was increased in lung, uterus, brain, kidney and thymus of the mothers. No differences were detected in liver and spleen. Pinealectomy enhanced this effect in the uterus and lung. It is concluded that during pregnancy high levels of oxidative stress induce an increase in oxidative damage to lipids, which in some cases is inhibited by the antioxidative actions of pineal indoles.

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Insights in the Role of Lipids, Oxidative Stress and Inflammation in Rheumatoid Arthritis Unveiled by New Trends in Lipidomic Investigations

Antioxidants ◽

10.3390/antiox10010045 ◽

2021 ◽

Vol 10 (1) ◽

pp. 45

Author(s):

Helena Beatriz Ferreira ◽

Tânia Melo ◽

Artur Paiva ◽

Maria do Rosário Domingues

Keyword(s):

Rheumatoid Arthritis ◽

Oxidative Stress ◽

Lipid Peroxidation ◽

Lipid Profile ◽

Inflammatory Responses ◽

Molecular Level ◽

Lipid Hydroperoxides ◽

Lipid Species ◽

Inflammatory Autoimmune Disease

Rheumatoid arthritis (RA) is a highly debilitating chronic inflammatory autoimmune disease most prevalent in women. The true etiology of this disease is complex, multifactorial, and is yet to be completely elucidated. However, oxidative stress and lipid peroxidation are associated with the development and pathogenesis of RA. In this case, oxidative damage biomarkers have been found to be significantly higher in RA patients, associated with the oxidation of biomolecules and the stimulation of inflammatory responses. Lipid peroxidation is one of the major consequences of oxidative stress, with the formation of deleterious lipid hydroperoxides and electrophilic reactive lipid species. Additionally, changes in the lipoprotein profile seem to be common in RA, contributing to cardiovascular diseases and a chronic inflammatory environment. Nevertheless, changes in the lipid profile at a molecular level in RA are still poorly understood. Therefore, the goal of this review was to gather all the information regarding lipid alterations in RA analyzed by mass spectrometry. Studies on the variation of lipid profile in RA using lipidomics showed that fatty acid and phospholipid metabolisms, especially in phosphatidylcholine and phosphatidylethanolamine, are affected in this disease. These promising results could lead to the discovery of new diagnostic lipid biomarkers for early diagnosis of RA and targets for personalized medicine.

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Malondialdehyde levels can be measured in serum and saliva by using a fast HPLC method with visible detection / Determinarea printr-o metodă HPLC-VIS rapidă a concentraţiilor serice şi salivare ale malondialdehidei

Revista Romana de Medicina de Laborator ◽

10.1515/rrlm-2016-0029 ◽

2016 ◽

Vol 24 (3) ◽

pp. 319-326 ◽

Cited By ~ 1

Author(s):

Erzsébet Fogarasi ◽

Mircea Dumitru Croitoru ◽

Ibolya Fülöp ◽

Enikő Nemes-Nagy ◽

Robert Gabriel Tripon ◽

...

Keyword(s):

Oxidative Stress ◽

Lipid Peroxidation ◽

Free Radicals ◽

Unsaturated Fatty Acids ◽

Pearson Correlation ◽

Living Organism ◽

Hplc Method ◽

Limit Of Quantification ◽

Pearson Correlation Test ◽

Repeated Sample

Abstract Oxidative stress appears when the amount of free radicals that are formed in a living organism exceed its spin-trapping ability. One of the most dangerous free radicals that are formed in the human body is the hydroxyl radical. It can alter several biomolecules, including the unsaturated fatty acids; this process is known as lipid peroxidation and can lead to cell necrosis and generation of several harmful byproducts including malondialdehyde, which serves also as a biomarker of oxidative stress. A new HPLC method with visible detection was developed for the detection of malondialdehyde in human serum and saliva samples. The method was verified in terms of specificity, linearity, limits of detection (0.35 ng/ml), limit of quantification (1.19 ng/ml), recovery (90.13±10.25 – 107.29±14.33) and precision (3.84±1.49% – 6.66±1.76%). An analysis time of only 1 minute was obtained and no interferences from the matrices were observed. Statistical analysis (Pearson correlation test) showed a moderate correlation (R = 0.5061, p = 0.0099) between serum and saliva concentrations (N = 25). The possibility of measuring salivary concentrations of malondialdehyde extents the applications of oxidative stress/lipid peroxidation estimations to categories of population unreachable before (pregnant women, small children, etc); repeated sample studies are also easier to make.

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