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Molecular Mechanisms of the Protective Role of Wheat Germ Oil Against Oxidative Stress–Induced Liver Disease
Chapter 19
Molecular Mechanisms of the Protective Role of Wheat Germ Oil Against Oxidative Stress–Induced Liver Disease El-Sayed Akool Pharmacology and Toxicology Department, Faculty of Pharmacy, Al-Azhar University, Cairo, Egypt
1. INTRODUCTION Free radicals are molecules that have an unpaired electron. Therefore, they are usually very reactive and unstable. There are two types of free radicals: oxygen free radicals or what is called reactive oxygen species (ROS) and reactive nitrogen species (RNS). The physiological levels of ROS and RNS in the biological system are required to perform certain functions. The generation of ROS is a natural part of aerobic life that plays an important role in defense against invading microorganisms, signal transduction pathways, and gene expression involved in cellular growth or death.1 The tight balance between ROS production and the endogenous antioxidant defense is essential to maintain the structural and functional integrity of different cell types. Several enzymes such as superoxide dismutase (SOD), catalase, and glutathione peroxidase, as well as nonenzymatic compounds such as tocopherol, vitamin E, β-carotene, ascorbic acid, and glutathione, play an important role in the protection against ROS.2,3 Overproduction of ROS and a consequent imbalance between oxidants and endogenously produced antioxidants have been reported to be responsible for various diseases such as cancer, neurodegenerative disorders, diabetes, cardiovascular diseases, and liver diseases.4 The liver is one of the most important organs in the human body. It is responsible for many critical functions including metabolism and detoxification of various endogenous and exogenous substances such as drugs as well as synthesis of essential proteins and lipids. The loss of those functions is usually accompanied with significant damage to the body. Overproduction of ROS plays an important role in the initiation and progression of liver disease. ROS has the ability to interact with all cellular macromolecules. It can interact to cleave the phosphodiester bonds holding bases in DNA. Lipids containing polyunsaturated fatty acids are also major targets for ROS in a process called lipid peroxidation that usually affects cell membrane, leading to disintegration of the cell and results in cell damage. Also, ROS plays an important role in fibrogenesis by increasing the fibrogenic growth factor, transforming growth factor-beta (TGF-β), and other cytokines such as interleukin-6 (IL-6) and tumor necrosis factor-alpha (TNF-α). Recently, ROS has been recognized as a major factor in the pathologic changes observed in liver diseases such as alcoholic hepatitis, nonalcoholic fatty liver disease, and chronic hepatitis C. ROS not only triggers hepatic damage via interaction with lipids, proteins, and DNA but also modulates different pathways that control normal biological system.5 In the last decade, natural products with high antioxidant activities have become popular worldwide for the prevention and management of liver diseases. Wheat germ oil (WGO) is one of the most important natural antioxidants because it contains high level of the most powerful antioxidant, vitamin E.6,7 It is also rich in flavonoids, sterols, octacosanols, and glutathione.8 WGO is also rich in unsaturated fatty acids, mainly oleic, linoleic, and α-linolenic acids that may attenuate oxidative damage.9 Interestingly, WGO intake usually results in a rapid increase in the tissue content of vitamin E and exerts high protection against oxidative damage.10,11 In recent years, WGO has attracted much attention due to its unique nutritional value. In this chapter, we tried to highlight the molecular mechanisms of the protective role of WGO against oxidative stress–induced liver disease.
2. REACTIVE OXYGEN SPECIES AND LIVER DISEASES The liver plays an important role in the metabolism of drugs, and increased drug intake enhances the production of ROS in these metabolic processes. It has been reported that a lot of drugs have the ability to induce oxidative stress including lipid peroxidation and depletion of antioxidants in the liver.12 For example, paracetamol that is commonly used to relieve pain and reduce fever has been shown to increase the by-product of lipid peroxidation malondialdehyde (MDA) content and nitrite as Dietary Interventions in Liver Disease. https://doi.org/10.1016/B978-0-12-814466-4.00019-7 Copyright © 2019 Elsevier Inc. All rights reserved.
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well as nitrate and decreased total SOD and Cu/Zn-SOD activities in the liver.13 In addition to paracetamol, the immunosuppressive agent cyclosporin A (CsA) has been reported to induce liver injury, which was associated with an increase in the serum levels of liver enzymes (ALT and AST).7 Furthermore, administration of CsA significantly increased hepatic MDA, iNOS, and NF-kB, while the activities of hepatic SOD and CAT as well as GSH content were highly reduced, suggesting a role of oxidative stress in hepatotoxicity induced by CsA.7 Also, generation of ROS by different anticancer drugs including doxorubicin and docetaxel has been recognized in the liver. Administration of these drugs significantly increased MDA content in the liver, and the administration of docetaxel significantly reduced SOD activity.14 The antiinflammatory sulfasalazine has also been found to induce ROS and subsequent oxidative damage in the liver. Administration of sulfasalazine significantly reduced SOD activity.15 In addition, the antituberculosis agent isoniazide (INH) has been demonstrated to induce both oxidative and nitrosative stress, but it was suggested that the highly reactive peroxynitrite (ONOO−), that is usually produced by the reaction between nitric oxide (NO) and superoxide (O2−), is responsible for hepatotoxicity induced by INH.16 Also, it has been reported that chronic administration of fluoxetine may cause oxidative damage in the liver.17 Also, in obese patients, a large amount of free fatty acids (FFAs) go directly into the liver. Fatty liver usually develops when the level of FFAs in hepatocytes exceeds the fatty acid β-oxidation capacity of the mitochondria and exceeds the excretion capacity of very low–density lipoproteins (VLDL) from the hepatocytes. The excessive amount of FFAs is usually metabolized in the hepatocytes resulting in overproduction of ROS and subsequent oxidative damage in the liver.18 Also hepatitis C virus (HCV) has been shown to induce ROS generation in hepatocytes.19,20 HCV infection has the ability to activate NADPH oxidase that generates ROS. This type of viral infection most frequently results in liver fibrosis, cirrhosis, and subsequent hepatocellular carcinoma (HCC). Measurement of the oxidative stress markers within the diseased liver revealed the presence of oxidative stress as indicated by significant reduction in the level of GSH. In addition, SOD and glutathione peroxidase activities were highly reduced. Furthermore, the by-product of lipid peroxidation MDA was highly increased in chronic HCV patients, indicating that ROS plays an important role in hepatic damage induced by HCV infection.21,22 Viral infection affects the cell redox equilibrium by generating ROS and by interfering with the synthesis of antioxidant enzymes. Furthermore, generation of ROS in the hepatocytes may lead to Kupffer cell activation and subsequent production of the profibrotic cytokine TGF-β.23 Also, it has been reported that ROS induced by viral hepatitis and subsequent TGF-β release play an important role in liver fibrosis.23 Alcohol consumption is also one of the causative agents that play an important role in the pathogenesis of chronic liver diseases. It has been reported that alcohol liver disease (ALD), accounting for an estimated 3.8% of global mortality, is associated with increased dose and time of alcohol intake.5 The spectrum of the disease most frequently includes hepatic steatosis, hepatitis, cirrhosis, and subsequent HCC. Ethanol and its metabolites have harmful effects on the liver. Recently, progress has been made in understanding the molecular mechanisms by which ethanol and its metabolites contribute to the pathogenesis of ALD. Ethanol is usually oxidized to acetaldehyde by the action of alcohol dehydrogenase, which is then further oxidized to acetate by the action of aldehyde dehydrogenase. Acetaldehyde has the ability to bind and form covalent chemical adducts with proteins, lipids, and DNA due to its electrophilic nature.5,24–27 These adducts alter cell homeostasis, changing protein structure and promoting DNA damage and mutation.27–29 Another metabolic pathway involved in ethanol degradation is the microsomal ethanol oxidizing system by cytochrome P450 enzymes. The 2E1 isoform of cytochrome P450 (CYP2E1) is responsible for alcohol breakdown in individuals who consume alcohol chronically. The catalytic reaction of CYP2E1 generates large amounts of ROS, such as superoxide anions and hydroxyl radicals, leading to oxidative stress resulting in hepatocytes injury and finally triggers various liver diseases. Several studies demonstrated that treatment of rats with alcohol significantly increased lipid peroxidation, while SOD, CAT, and glutathione peroxidase activities were highly reduced.30–32 Furthermore, the GSH levels in liver and blood of patients with ALD were highly reduced.32,33 Environmental pollutants have also been involved in oxidative damage in the liver. It has been reported that mercury chloride significantly attenuated the endogenous antioxidant system. Mn-dependent SOD and Cu- and Zn-dependent SOD as well as CAT and glutathione peroxidase were highly reduced. This reduction in the endogenous antioxidant defense system was accompanied by an increase in serum ALT level.34 Not only mercury but also lead was found to induce lipid peroxidation in a ROS-dependent manner.35 Nicotine has also been reported to induce oxidative stress in the liver. Cigarette smoking and nicotine replacement therapies are the major sources of human exposure to nicotine. Each cigarette has 10–25 mg of nicotine, and the peak plasma nicotine level is usually higher than that of replacement therapy.36 The 2A6 isoform of cytochrome P450 (CYP2A6) is involved in the metabolic inactivation of nicotine in the liver. The formation of electrophilic metabolite and its ability to bind with nucleophilic constituents of the cell generate ROS.37,38 Radiation has also been shown to induce hepatic oxidative stress. It has been reported that exposure to mobile phonelike radiation significantly increased nitric oxide and the by-product of lipid peroxidation MDA and decreased enzymatic activities of SOD and glutathione peroxidase in the liver of guinea pigs.39 Furthermore, it has been shown that oxidative damage was increased along with the duration of radiation exposure.
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3. WHEAT GERM OIL AND LIVER DISEASES Liver disease is one of the leading causes of death. It remains a major health problem around the world. In chronic liver diseases, current therapeutic strategies are limited and the only available treatment is liver transplantation for end-stage liver disease. However, natural-based preparations are successfully used for the management of hepatic diseases. As mentioned before, prolonged imbalance in the liver between the production of ROS and their elimination by protective mechanisms (endogenous antioxidants) leads to hepatic damage. Thus, it was interesting to find that natural compounds have the ability to interfere directly or indirectly with the pro-oxidant process. Among the wide range of natural sources, plant sources have become popular worldwide, where 65% of patients in Europe and the United States used herbal preparations for the management of liver diseases.40 One of the most important natural compounds of plant origin is WGO.
3.1 Nutritional Composition Wheat is usually milled to produce flour and other products. Wheat germ (2%–3% of grain) can be separated as a by-product during wheat milling. The by-product wheat germ can be used in different applications such as food and pharmaceutical purposes.41 The germ contains high amounts of protein (25%), sugar (18%), oil (16% of the embryonic axis and 32% of the scutellum), and ash (5%).42 WGO is rich in phosphorus (1.4 g/kg), contains no starch but high content of vitamins E and B.42,43 WGO is an excellent source of natural vitamin E, the most powerful natural antioxidant. The tocopherol content of WGO is generally higher than other vegetable oils. It can reach up to 2500 mg/kg, and α-tocopherol (60%) is predominant.42,44 Vitamin E is one of the most important nutrient for humans because it is essential for the prevention of several disorders, including peripheral neuropathy and hemolytic anemia.45 Also, vitamin E has the ability to prevent oxidative damage in biological systems.46 Supplementation of vitamin E prevents DNA damage due to its free radical scavenging activity.47,48 Furthermore, the hepatoprotective effect of vitamin E against oxidative damage induced by cisplatin has been reported.49 WGO is also rich in flavonoids, sterols, octacosanols, and glutathione.8 It has been reported that flavonoids have several health benefits such as antioxidant, antiproliferative, antiinflammatory, and anticancer activities as well as antihypertensive effects.50 Furthermore, the flavonoid compound luteolin has been shown to protect against methanol-induced oxidative damage in liver tissue.51 It is also rich in unsaturated fatty acids, mainly oleic, linoleic, and α-linolenic acids, that may attenuate oxidative damage.9 Interestingly, administration of WGO usually results in a rapid increase in the tissue content of vitamin E and exerts high protection against oxidative damage.10,11 In recent years, WGO has attracted much attention due to its unique nutritional value, especially the high level of vitamin E, the most powerful natural antioxidant.
3.2 Antioxidant Activity Several studies have focused on WGO due to its unique character and examined its antioxidant activity against oxidative stress–induced hepatic damage. In 2015, it has been shown that WGO has the ability to protect against oxidative stress and hepatotoxicity induced by cyclosporine A (CsA).7 CsA is one of the most efficient immunosuppressive agents. However, its clinical use is limited by several side effects including hepatotoxicity. It has been reported that CsA induces liver toxicity via generation of ROS and subsequent imbalance between oxidants and endogenously produced antioxidants.52 In this study, it was found that WGO has the ability to protect against oxidative stress and hepatotoxicity induced by the immunosuppressive agent CsA as indicated by the improvement not only in the serum levels of liver enzymes but also in histopathological changes. These effects of WGO were associated with an increase in the endogenous antioxidants GSH, SOD, and CAT as well as inhibition of lipid peroxidation, iNOS, and NF-kB expression. The author suggests that hepatoprotective effect of WGO may be attributed to its ability to restore the balance between oxygen radical production and the endogenous antioxidant defense system which was disturbed by CsA in the liver tissue. Furthermore, the author demonstrates that the immunosuppressive efficiency of CsA was not altered in the presence of WGO. In other study, it has been reported that WGO has the ability to protect the liver from CCl4 damage. The hepatotoxicity of CCl4 is well documented. The generation of free radicals from CCl4 and its metabolites has the ability to induce an impairment of the endoplasmic reticulum and altered the permeability of the mitochondrial membrane, resulting in lipids accumulation, reduction of protein synthesis, and overproduction of the oxidative stress.53,54 In this study, it has been demonstrated that administration of WGO clearly protected the liver in acute CCl4-induced hepatic damage. The author suggests that the protective effect of WGO is attributed to its ability to reduce the lipid profile and suppressing the oxidative stress that caused DNA damage. In further study, WGO has shown to protect against doxorubicin-induced hepatotoxicity in mice. Doxorubicin is one of the most important anticancer agents. However, the use of doxorubicin is limited due to its adverse effects.
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Doxorubicin can have serious adverse effects in the liver due to its ability to generate ROS, which leads to tissue damage. In this study, WGO was found to be able to attenuate hepatotoxicity and pathological changes induced by doxorubicin as indicated by a clear reduction in apoptotic index in hepatocytes of animals treated with doxorubicin plus WGO compared with doxorubicin alone–treated animals.55 Also, WGO has been shown to attenuate liver toxicity induced by sodium nitrate in rats.56 Sodium nitrate is commonly used as agricultural fertilizers that reach to humans and animals by different routes.57,58 Ingestion of food and drinking water represents the major source of nitrate in human body. The presence of nitrate in foods and water is a serious threat to the health of people. Approximately 5% of ingested nitrate is converted to the more toxic nitrite in gastrointestinal tract by the action of microflora.59 Nitrite as well as N-nitroso compounds that have also been formed are toxic and can lead to severe pathological changes in human body. In this study, it was found that administration of WGO can protect the liver against free radical damage induced by sodium nitrate in animals. In 2014, the hepatoprotective and antioxidant activities of WGO against oxidative stress induced by nicotine have been reported.60 In this study, oral administration of WGO effectively reduced the oxidative damage induced by nicotine in the liver tissue as indicated by a significant reduction in the by-product of lipid peroxidation MDA and liver enzymes in serum. Furthermore, WGO significantly improved the histopathological lesions induced by nicotine in liver tissue. Moreover, SOD as well as glutathione peroxidase activities were highly increased in liver tissues of animals treated with nicotine plus WGO compared with nicotine alone–treated animals. The authors recommended WGO to be given to individuals who are exposed to nicotine. Also, the hepatoprotective effect of WGO against clozapine-induced oxidative damage in rat liver was reported. The antipsychotic drug clozapine has been shown to generate ROS. In this work, the authors demonstrate that WGO significantly improved the biochemical markers of oxidative damage induced by clozapine in liver tissue.61 The prophylactic role of WGO in combination with ginseng against liver toxicity induced by radiation has also been reported.62 In this study, irradiation of rats showed a significant increase in serum liver enzymes associated with decrease in the serum content of total protein and albumin indicating acute hepatotoxicity. In addition, radiation induced an elevation of lipid peroxidation in plasma and liver. However, the rats that received WGO and panax ginseng supplement showed a significant improvement in the serum markers of liver damage as well as significant reduction in lipid peroxidation in the liver. The authors suggest that combination therapy of WGO and panax ginseng might be useful against radiation-induced oxidative stress and subsequent tissue damage. Furthermore, it has been shown that WGO has the ability to protect against liver toxicity induced by methotrexate in mice.63 In this study, a single dose of methotrexate was enough to induce oxidative stress in liver tissue. The findings of this study confirmed that WGO has the ability to protect against oxidative damage induced by methotrexate in the liver by improving the serum liver enzymes levels, enhancing antioxidant defense status, and reducing the by-product of lipid peroxidation MDA. The author here recommended WGO supplementation to individuals who are treated with methotrexate. The hepatoprotective effect of WGO in combination with carrot against benzene-induced liver toxicity has also been reported.64 This experimental study was carried out on rats injected with benzene and given diet supplemented with carrot and WGO. This combination (WGO plus carrot) significantly inhibited oxidative stress induced by benzene in the liver as indicated by a significant decrease in the by-product of lipid peroxidation MDA and an increase in the level of endogenous antioxidant enzymes as well as a significant improvement in liver tissue compared with rats treated with benzene alone. Finally, WGO can be considered as one of the most important natural antioxidants and hepatoprotective agents that may work efficiently against oxidative stress and subsequent hepatic damage. A daily dose of WGO is the perfect way to enrich diet with a high concentration of the most powerful natural antioxidant vitamin E that may protect the liver through its unique cytoprotective properties.
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Molecular Mechanisms of the Protective Role of Wheat Germ Oil Against Oxidative Stress–Induced Liver Disease El-Sayed Akool Pharmacology and Toxicology Department, Faculty of Pharmacy, Al-Azhar University, Cairo, Egypt
1. INTRODUCTION Free radicals are molecules that have an unpaired electron. Therefore, they are usually very reactive and unstable. There are two types of free radicals: oxygen free radicals or what is called reactive oxygen species (ROS) and reactive nitrogen species (RNS). The physiological levels of ROS and RNS in the biological system are required to perform certain functions. The generation of ROS is a natural part of aerobic life that plays an important role in defense against invading microorganisms, signal transduction pathways, and gene expression involved in cellular growth or death.1 The tight balance between ROS production and the endogenous antioxidant defense is essential to maintain the structural and functional integrity of different cell types. Several enzymes such as superoxide dismutase (SOD), catalase, and glutathione peroxidase, as well as nonenzymatic compounds such as tocopherol, vitamin E, β-carotene, ascorbic acid, and glutathione, play an important role in the protection against ROS.2,3 Overproduction of ROS and a consequent imbalance between oxidants and endogenously produced antioxidants have been reported to be responsible for various diseases such as cancer, neurodegenerative disorders, diabetes, cardiovascular diseases, and liver diseases.4 The liver is one of the most important organs in the human body. It is responsible for many critical functions including metabolism and detoxification of various endogenous and exogenous substances such as drugs as well as synthesis of essential proteins and lipids. The loss of those functions is usually accompanied with significant damage to the body. Overproduction of ROS plays an important role in the initiation and progression of liver disease. ROS has the ability to interact with all cellular macromolecules. It can interact to cleave the phosphodiester bonds holding bases in DNA. Lipids containing polyunsaturated fatty acids are also major targets for ROS in a process called lipid peroxidation that usually affects cell membrane, leading to disintegration of the cell and results in cell damage. Also, ROS plays an important role in fibrogenesis by increasing the fibrogenic growth factor, transforming growth factor-beta (TGF-β), and other cytokines such as interleukin-6 (IL-6) and tumor necrosis factor-alpha (TNF-α). Recently, ROS has been recognized as a major factor in the pathologic changes observed in liver diseases such as alcoholic hepatitis, nonalcoholic fatty liver disease, and chronic hepatitis C. ROS not only triggers hepatic damage via interaction with lipids, proteins, and DNA but also modulates different pathways that control normal biological system.5 In the last decade, natural products with high antioxidant activities have become popular worldwide for the prevention and management of liver diseases. Wheat germ oil (WGO) is one of the most important natural antioxidants because it contains high level of the most powerful antioxidant, vitamin E.6,7 It is also rich in flavonoids, sterols, octacosanols, and glutathione.8 WGO is also rich in unsaturated fatty acids, mainly oleic, linoleic, and α-linolenic acids that may attenuate oxidative damage.9 Interestingly, WGO intake usually results in a rapid increase in the tissue content of vitamin E and exerts high protection against oxidative damage.10,11 In recent years, WGO has attracted much attention due to its unique nutritional value. In this chapter, we tried to highlight the molecular mechanisms of the protective role of WGO against oxidative stress–induced liver disease.
2. REACTIVE OXYGEN SPECIES AND LIVER DISEASES The liver plays an important role in the metabolism of drugs, and increased drug intake enhances the production of ROS in these metabolic processes. It has been reported that a lot of drugs have the ability to induce oxidative stress including lipid peroxidation and depletion of antioxidants in the liver.12 For example, paracetamol that is commonly used to relieve pain and reduce fever has been shown to increase the by-product of lipid peroxidation malondialdehyde (MDA) content and nitrite as Dietary Interventions in Liver Disease. https://doi.org/10.1016/B978-0-12-814466-4.00019-7 Copyright © 2019 Elsevier Inc. All rights reserved.
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well as nitrate and decreased total SOD and Cu/Zn-SOD activities in the liver.13 In addition to paracetamol, the immunosuppressive agent cyclosporin A (CsA) has been reported to induce liver injury, which was associated with an increase in the serum levels of liver enzymes (ALT and AST).7 Furthermore, administration of CsA significantly increased hepatic MDA, iNOS, and NF-kB, while the activities of hepatic SOD and CAT as well as GSH content were highly reduced, suggesting a role of oxidative stress in hepatotoxicity induced by CsA.7 Also, generation of ROS by different anticancer drugs including doxorubicin and docetaxel has been recognized in the liver. Administration of these drugs significantly increased MDA content in the liver, and the administration of docetaxel significantly reduced SOD activity.14 The antiinflammatory sulfasalazine has also been found to induce ROS and subsequent oxidative damage in the liver. Administration of sulfasalazine significantly reduced SOD activity.15 In addition, the antituberculosis agent isoniazide (INH) has been demonstrated to induce both oxidative and nitrosative stress, but it was suggested that the highly reactive peroxynitrite (ONOO−), that is usually produced by the reaction between nitric oxide (NO) and superoxide (O2−), is responsible for hepatotoxicity induced by INH.16 Also, it has been reported that chronic administration of fluoxetine may cause oxidative damage in the liver.17 Also, in obese patients, a large amount of free fatty acids (FFAs) go directly into the liver. Fatty liver usually develops when the level of FFAs in hepatocytes exceeds the fatty acid β-oxidation capacity of the mitochondria and exceeds the excretion capacity of very low–density lipoproteins (VLDL) from the hepatocytes. The excessive amount of FFAs is usually metabolized in the hepatocytes resulting in overproduction of ROS and subsequent oxidative damage in the liver.18 Also hepatitis C virus (HCV) has been shown to induce ROS generation in hepatocytes.19,20 HCV infection has the ability to activate NADPH oxidase that generates ROS. This type of viral infection most frequently results in liver fibrosis, cirrhosis, and subsequent hepatocellular carcinoma (HCC). Measurement of the oxidative stress markers within the diseased liver revealed the presence of oxidative stress as indicated by significant reduction in the level of GSH. In addition, SOD and glutathione peroxidase activities were highly reduced. Furthermore, the by-product of lipid peroxidation MDA was highly increased in chronic HCV patients, indicating that ROS plays an important role in hepatic damage induced by HCV infection.21,22 Viral infection affects the cell redox equilibrium by generating ROS and by interfering with the synthesis of antioxidant enzymes. Furthermore, generation of ROS in the hepatocytes may lead to Kupffer cell activation and subsequent production of the profibrotic cytokine TGF-β.23 Also, it has been reported that ROS induced by viral hepatitis and subsequent TGF-β release play an important role in liver fibrosis.23 Alcohol consumption is also one of the causative agents that play an important role in the pathogenesis of chronic liver diseases. It has been reported that alcohol liver disease (ALD), accounting for an estimated 3.8% of global mortality, is associated with increased dose and time of alcohol intake.5 The spectrum of the disease most frequently includes hepatic steatosis, hepatitis, cirrhosis, and subsequent HCC. Ethanol and its metabolites have harmful effects on the liver. Recently, progress has been made in understanding the molecular mechanisms by which ethanol and its metabolites contribute to the pathogenesis of ALD. Ethanol is usually oxidized to acetaldehyde by the action of alcohol dehydrogenase, which is then further oxidized to acetate by the action of aldehyde dehydrogenase. Acetaldehyde has the ability to bind and form covalent chemical adducts with proteins, lipids, and DNA due to its electrophilic nature.5,24–27 These adducts alter cell homeostasis, changing protein structure and promoting DNA damage and mutation.27–29 Another metabolic pathway involved in ethanol degradation is the microsomal ethanol oxidizing system by cytochrome P450 enzymes. The 2E1 isoform of cytochrome P450 (CYP2E1) is responsible for alcohol breakdown in individuals who consume alcohol chronically. The catalytic reaction of CYP2E1 generates large amounts of ROS, such as superoxide anions and hydroxyl radicals, leading to oxidative stress resulting in hepatocytes injury and finally triggers various liver diseases. Several studies demonstrated that treatment of rats with alcohol significantly increased lipid peroxidation, while SOD, CAT, and glutathione peroxidase activities were highly reduced.30–32 Furthermore, the GSH levels in liver and blood of patients with ALD were highly reduced.32,33 Environmental pollutants have also been involved in oxidative damage in the liver. It has been reported that mercury chloride significantly attenuated the endogenous antioxidant system. Mn-dependent SOD and Cu- and Zn-dependent SOD as well as CAT and glutathione peroxidase were highly reduced. This reduction in the endogenous antioxidant defense system was accompanied by an increase in serum ALT level.34 Not only mercury but also lead was found to induce lipid peroxidation in a ROS-dependent manner.35 Nicotine has also been reported to induce oxidative stress in the liver. Cigarette smoking and nicotine replacement therapies are the major sources of human exposure to nicotine. Each cigarette has 10–25 mg of nicotine, and the peak plasma nicotine level is usually higher than that of replacement therapy.36 The 2A6 isoform of cytochrome P450 (CYP2A6) is involved in the metabolic inactivation of nicotine in the liver. The formation of electrophilic metabolite and its ability to bind with nucleophilic constituents of the cell generate ROS.37,38 Radiation has also been shown to induce hepatic oxidative stress. It has been reported that exposure to mobile phonelike radiation significantly increased nitric oxide and the by-product of lipid peroxidation MDA and decreased enzymatic activities of SOD and glutathione peroxidase in the liver of guinea pigs.39 Furthermore, it has been shown that oxidative damage was increased along with the duration of radiation exposure.
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3. WHEAT GERM OIL AND LIVER DISEASES Liver disease is one of the leading causes of death. It remains a major health problem around the world. In chronic liver diseases, current therapeutic strategies are limited and the only available treatment is liver transplantation for end-stage liver disease. However, natural-based preparations are successfully used for the management of hepatic diseases. As mentioned before, prolonged imbalance in the liver between the production of ROS and their elimination by protective mechanisms (endogenous antioxidants) leads to hepatic damage. Thus, it was interesting to find that natural compounds have the ability to interfere directly or indirectly with the pro-oxidant process. Among the wide range of natural sources, plant sources have become popular worldwide, where 65% of patients in Europe and the United States used herbal preparations for the management of liver diseases.40 One of the most important natural compounds of plant origin is WGO.
3.1 Nutritional Composition Wheat is usually milled to produce flour and other products. Wheat germ (2%–3% of grain) can be separated as a by-product during wheat milling. The by-product wheat germ can be used in different applications such as food and pharmaceutical purposes.41 The germ contains high amounts of protein (25%), sugar (18%), oil (16% of the embryonic axis and 32% of the scutellum), and ash (5%).42 WGO is rich in phosphorus (1.4 g/kg), contains no starch but high content of vitamins E and B.42,43 WGO is an excellent source of natural vitamin E, the most powerful natural antioxidant. The tocopherol content of WGO is generally higher than other vegetable oils. It can reach up to 2500 mg/kg, and α-tocopherol (60%) is predominant.42,44 Vitamin E is one of the most important nutrient for humans because it is essential for the prevention of several disorders, including peripheral neuropathy and hemolytic anemia.45 Also, vitamin E has the ability to prevent oxidative damage in biological systems.46 Supplementation of vitamin E prevents DNA damage due to its free radical scavenging activity.47,48 Furthermore, the hepatoprotective effect of vitamin E against oxidative damage induced by cisplatin has been reported.49 WGO is also rich in flavonoids, sterols, octacosanols, and glutathione.8 It has been reported that flavonoids have several health benefits such as antioxidant, antiproliferative, antiinflammatory, and anticancer activities as well as antihypertensive effects.50 Furthermore, the flavonoid compound luteolin has been shown to protect against methanol-induced oxidative damage in liver tissue.51 It is also rich in unsaturated fatty acids, mainly oleic, linoleic, and α-linolenic acids, that may attenuate oxidative damage.9 Interestingly, administration of WGO usually results in a rapid increase in the tissue content of vitamin E and exerts high protection against oxidative damage.10,11 In recent years, WGO has attracted much attention due to its unique nutritional value, especially the high level of vitamin E, the most powerful natural antioxidant.
3.2 Antioxidant Activity Several studies have focused on WGO due to its unique character and examined its antioxidant activity against oxidative stress–induced hepatic damage. In 2015, it has been shown that WGO has the ability to protect against oxidative stress and hepatotoxicity induced by cyclosporine A (CsA).7 CsA is one of the most efficient immunosuppressive agents. However, its clinical use is limited by several side effects including hepatotoxicity. It has been reported that CsA induces liver toxicity via generation of ROS and subsequent imbalance between oxidants and endogenously produced antioxidants.52 In this study, it was found that WGO has the ability to protect against oxidative stress and hepatotoxicity induced by the immunosuppressive agent CsA as indicated by the improvement not only in the serum levels of liver enzymes but also in histopathological changes. These effects of WGO were associated with an increase in the endogenous antioxidants GSH, SOD, and CAT as well as inhibition of lipid peroxidation, iNOS, and NF-kB expression. The author suggests that hepatoprotective effect of WGO may be attributed to its ability to restore the balance between oxygen radical production and the endogenous antioxidant defense system which was disturbed by CsA in the liver tissue. Furthermore, the author demonstrates that the immunosuppressive efficiency of CsA was not altered in the presence of WGO. In other study, it has been reported that WGO has the ability to protect the liver from CCl4 damage. The hepatotoxicity of CCl4 is well documented. The generation of free radicals from CCl4 and its metabolites has the ability to induce an impairment of the endoplasmic reticulum and altered the permeability of the mitochondrial membrane, resulting in lipids accumulation, reduction of protein synthesis, and overproduction of the oxidative stress.53,54 In this study, it has been demonstrated that administration of WGO clearly protected the liver in acute CCl4-induced hepatic damage. The author suggests that the protective effect of WGO is attributed to its ability to reduce the lipid profile and suppressing the oxidative stress that caused DNA damage. In further study, WGO has shown to protect against doxorubicin-induced hepatotoxicity in mice. Doxorubicin is one of the most important anticancer agents. However, the use of doxorubicin is limited due to its adverse effects.
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Doxorubicin can have serious adverse effects in the liver due to its ability to generate ROS, which leads to tissue damage. In this study, WGO was found to be able to attenuate hepatotoxicity and pathological changes induced by doxorubicin as indicated by a clear reduction in apoptotic index in hepatocytes of animals treated with doxorubicin plus WGO compared with doxorubicin alone–treated animals.55 Also, WGO has been shown to attenuate liver toxicity induced by sodium nitrate in rats.56 Sodium nitrate is commonly used as agricultural fertilizers that reach to humans and animals by different routes.57,58 Ingestion of food and drinking water represents the major source of nitrate in human body. The presence of nitrate in foods and water is a serious threat to the health of people. Approximately 5% of ingested nitrate is converted to the more toxic nitrite in gastrointestinal tract by the action of microflora.59 Nitrite as well as N-nitroso compounds that have also been formed are toxic and can lead to severe pathological changes in human body. In this study, it was found that administration of WGO can protect the liver against free radical damage induced by sodium nitrate in animals. In 2014, the hepatoprotective and antioxidant activities of WGO against oxidative stress induced by nicotine have been reported.60 In this study, oral administration of WGO effectively reduced the oxidative damage induced by nicotine in the liver tissue as indicated by a significant reduction in the by-product of lipid peroxidation MDA and liver enzymes in serum. Furthermore, WGO significantly improved the histopathological lesions induced by nicotine in liver tissue. Moreover, SOD as well as glutathione peroxidase activities were highly increased in liver tissues of animals treated with nicotine plus WGO compared with nicotine alone–treated animals. The authors recommended WGO to be given to individuals who are exposed to nicotine. Also, the hepatoprotective effect of WGO against clozapine-induced oxidative damage in rat liver was reported. The antipsychotic drug clozapine has been shown to generate ROS. In this work, the authors demonstrate that WGO significantly improved the biochemical markers of oxidative damage induced by clozapine in liver tissue.61 The prophylactic role of WGO in combination with ginseng against liver toxicity induced by radiation has also been reported.62 In this study, irradiation of rats showed a significant increase in serum liver enzymes associated with decrease in the serum content of total protein and albumin indicating acute hepatotoxicity. In addition, radiation induced an elevation of lipid peroxidation in plasma and liver. However, the rats that received WGO and panax ginseng supplement showed a significant improvement in the serum markers of liver damage as well as significant reduction in lipid peroxidation in the liver. The authors suggest that combination therapy of WGO and panax ginseng might be useful against radiation-induced oxidative stress and subsequent tissue damage. Furthermore, it has been shown that WGO has the ability to protect against liver toxicity induced by methotrexate in mice.63 In this study, a single dose of methotrexate was enough to induce oxidative stress in liver tissue. The findings of this study confirmed that WGO has the ability to protect against oxidative damage induced by methotrexate in the liver by improving the serum liver enzymes levels, enhancing antioxidant defense status, and reducing the by-product of lipid peroxidation MDA. The author here recommended WGO supplementation to individuals who are treated with methotrexate. The hepatoprotective effect of WGO in combination with carrot against benzene-induced liver toxicity has also been reported.64 This experimental study was carried out on rats injected with benzene and given diet supplemented with carrot and WGO. This combination (WGO plus carrot) significantly inhibited oxidative stress induced by benzene in the liver as indicated by a significant decrease in the by-product of lipid peroxidation MDA and an increase in the level of endogenous antioxidant enzymes as well as a significant improvement in liver tissue compared with rats treated with benzene alone. Finally, WGO can be considered as one of the most important natural antioxidants and hepatoprotective agents that may work efficiently against oxidative stress and subsequent hepatic damage. A daily dose of WGO is the perfect way to enrich diet with a high concentration of the most powerful natural antioxidant vitamin E that may protect the liver through its unique cytoprotective properties.
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