Liver diseases are most common disorders in the world and characterized by rapid changes from steatosis to chronic hepatitis, fibrosis, cirrhosis, and hepatocellular carcinoma (HCC). Natural products that attained great attention is to be used in the prevention and treatment of multiple diseases in humans. Several researches have been reported numerous natural and phytochemical compounds that may counteract or prevent the hepatic injury and primary liver cancer. The conservative treatment of liver toxicity and HCC may face awkward challenges in chemotherapy such as therapeutic failure or drug resistance. Accordingly, there is an actual need for safe and effective therapeutic and preventive modalities for liver disorders. The present review aims to focus on the potential protective and therapeutic effects of natural compounds in prevention and treatment of hepatotoxicity and HCC. It also demonstrates the mechanism of the natural products in enzymatic regulation of antioxidants and its role in apoptosis and proliferation of cancerous lesions of hepatocytes. Accordingly, it highlights the promising role of natural bioactive compounds and provides the rational for further transitional researches, and emphasize on the scientific validation of natural compounds for therapeutic portfolio for clinical use in liver diseases.
Keywords: Antioxidant; hepatocellular carcinoma; hepatotoxicity; liver; natural compounds
Chronic liver diseases are common worldwide disorders characterized by bad sequels started with steatosis to chronic hepatitis, fibrosis, cirrhosis, and hepatocellular carcinoma (HCC).[1,2] Indeed, HCC is the fifth most commonly leading cancer, the major cause of death in patients with liver cirrhosis, and the second common cause of cancer-related death in the world.
The major target strategy in the treatment of liver diseases is to terminate the serial consequences at the pre-fibrotic stage of the liver.  To date, modern medicines have little to offer for alleviation of hepatic diseases. However, natural based preparations are successfully employed for the treatment of liver disorders. Accordingly, there is an increased attention in natural products that may counteract the detrimental effects of environmental or chemical toxic compounds and prevent multiple hepatic disorders in humans.
Polyphenols, commonly presented in vegetables, herbs, seeds, fruits and other natural sources, represent more than 8,000 different compounds, classified in different classes based on their chemical structure, they are composed of at least one aromatic ring with one or more hydroxyl groups attached. Polyphenols may be a promising candidate for preventing ethanol-induced liver injury through regulating alcohol metabolic enzymes in a cyclic AMP-dependent manner, polyphenols play a crucial role in protection of liver against hepatitis due to its potential activity in reduction of early proinflammatory cytokines [tumor necrosis factor-α and interleukin (IL)-1β], activation of anti-inflammatory IL-10, and inhibition lipopolysaccharide-induced activation of nuclear factor kappa B (NF-κB) in hepatocytes. Polyphenols are composed of two formulas; phenolic acids and flavonoids, and account for 60% and 30%, respectively, of dietary polyphenols.
Phenolic compounds (PhCs), which are ubiquitously found in plants, have a potent antioxidant activity mainly due to their ability in redox reactions, so they act as reducing agents, singlet oxygen quenchers, hydrogen donators, and chelating agents of metal ions. Moreover, previous studies revealed that PhCs play an important role in the prevention of hepatotoxicity through increase in the level of reduced glutathione (GSH).
Flavonoids are a group of polyphenolic compounds, different in chemical structure and characteristics, naturally founded in plants. More than 9000 different flavonoid compounds were described in plants till now and they play major biological roles through affecting several developmental and important processes.
Flavonoids showed versatile health benefits such as anti-inflammatory, antioxidant, antiproliferative and anticancer activity, free radical scavenging activity, antihypertensive effects. It has been reported that one of the flavonoid compounds; luteolin shows a hepatoprotective effect and antioxidant properties against methanol hepatotoxicity.
Milk thistle (Silybum marianum) is one of the most famous herbal agents used to treat liver diseases since the 16th century. Major constituents of Milk thistle are the flavonoids, such as silibinin, silidianin, silichristin, and isosilibinin. Silymarin showed antioxidant properties and hepatoprotective activity, through inhibition of lipid peroxidation, depletion of liver GSH, inhibition of gentotoxicity, and enhancement of hepatogenesis.
Glycyrrhizin, the active constituent obtained from aqueous extraction of the liquorice root (Glycyrrhiza glabra), has been used in traditional medicine to alleviate bronchitis, gastritis, and jaundice. The major constituents of licorice are glycyrrhetic acid, flavonoids, hydroxycoumarins, and beta-sitosterol. The latter is likely possessing glucocorticoid and mineralocorticoid properties. Licorice and their products have been reported to be useful in treatment of human hepatitis, animal inducible hepatocarcinogenesis and attenuate titanium dioxide nanoparticles-induced hepatotoxicity.[17,18]
Ginseng (Panax ginseng) a valued Chinese and Korean traditional medicinal herb, has been clinically used in China for thousands of years. Red ginseng elicits a protection against aflatoxin B1 and fumonisins-induced hepatic pre-cancerous lesions in rats and synergistic action with honey against CCl4-induced hepatonephrotoxicity.[19,20]
Ginkgo biloba extract has been shown antioxidant property due to its ability to scavenge free radicals and inhibition of lipid peroxidation. The most recent discovered G. biloba components are polyphenols from which flavonoids and terpene lactones were derived and widely used for treating cardiovascular, non-alcoholic fatty liver, and cerebrovascular diseases.[22-24]
Dandelion (Taraxacum officinale), dandelion water extract (DWE), a herbal medication, may have an effect on the activity of messenger RNA expression of hepatic antioxidant enzymes due to its components that includes sesquiterpene lactones, phenylpropanoids, triterpenoid saponins and modify lipid profile in streptozotocin-induced diabetes in rats.[25-27] It has been reported that DWE has antifibrotic effect through inactivation of hepatic stellate cells and the enhancement of hepatic regenerative capabilities.
Garlic (Allium sativum) has been widely used as a foodstuff and a traditional medicine for many centuries throughout the world. Garlic is available in different forms such as powder or garlic oil. Garlic has a beneficial value such as antiatherosclerotic, antihypertensive, antimicrobial, anticancer, immunomodulatory, antioxidant, and radioprotectector effects. On the other hand, allicin (diallythiosulfonate), which is the main biologically active component of freshly crushed garlic cloves, has been produced by the interaction of the non-protein amino acid alliin with the enzyme alliinase (alliin lyase). It has antihepatocarcinogenic effect through the p53 gene modulating apoptosis and autophagy.
Turmeric (Curcuma longa) has been found in the Far East and tropical regions. It had been used to treat menstrual disorders, colic, inflammation, bruising, dyspepsia, haematuria, and flatulence. It has also anticancer and antioxidant actions due to the presence of three chemical components e.g. curcumin I, II, and III. It suppresses the activation of NF-κB, so it may be useful in preventing liver disease such as hepatonephrotoxicity.
Colchicine (Colchicum autumnale) is the major alkaloid obtained from C. autumnale. Pharmacological properties of colchicine included antimitotic effects and can be used for the treatment of gout. Moreover, colchicine has been acts as antitumor agent. Colchicine has been reported to be a safe antifibrotic agent when used for long-term treatment of liver disease.
Thyme (Thymus vulgaris) is cultivated in Central and Southern Europe, Africa, and Asia. It is rich with essential oils and antioxidative phenolic substances. It is widely used in folk medicine for the treatment of a variety of diseases including gastroenteric and bronchopulmonary disorders. It is also effective as anthelmintic, antispasmodic, carminative, sedative, diaphoretic, antimicrobial, antioxidant, and antifungal agents. T. vulgaris also showed hepatorenoprtective effects against aflatoxicosis in rats.
Marigold (Calendula officinalis) is an annual herb native to the Mediterranean region. In Europe and America, it is cultivated for ornamental and medicinal purposes. C. officinalis as the marigold or maravilla, and has been widely used in folk therapy. Calendula flower decoction or tincture showed more than 35 properties and its preparations have been used as valuable remedies for burns. C. officinalis is mainly used for cutaneous and internal inflammatory diseases of several origins. Its extract has a protective effect against UV-induced oxidative stress. It has been well documented that calendula extract showed antigenotoxicity and ameliorative effect against hepatotoxicity induced by aflatoxin due to high percentage of total PhCs.[6,41] The effect of herbal agents has been summarized at Table 1.
Table 1: Effect of herbal agents against hepatic disordersClick here to view
Micronutrients (vitamins and minerals)
Vitamin B12 (cyanocobalamin) molecule contains a cobalt complex, it is known as cobalamin. Molecular weight of vitamin B12 is the highest among all vitamins; therefore, it is known to accumulate at high levels in the liver. Vitamin B12 is a complex organometallic cofactor associated with three subfamilies of enzymes: the adenosyl cobalamin-dependent isomerases, the methyl cobalamin-dependent methyl transferases and the dehalogenases. In chronic feeding regimen without a methyl-donor, vitamin B12 may lead to the development of HCC. Previous studies reported that vitamin B12 showed hepatoprotective effect against dimethyl nitrosamine in intoxicated rats. Moreover, vitamin B12 suppresses genetic expression of α-smooth muscle actin and heat-shock protein 47, which are markers of liver fibrosis.
Vitamin C (ascorbic acid) is one of the most required nutrients for a variety of biological functions. The health-promoting effects of vitamin C can be attributed to its biological functions as a cofactor for a number of enzymes, most notably hydroxylases involved in collagen synthesis and as a water-soluble antioxidant. However, it can exert its antioxidant properties in both aqueous and non-aqueous environments. Vitamin C is able to decrease hepatic apoptosis and necrosis against cholestatic liver injury in experimental animals.
Vitamin E (α-Tocopherol) is a potent lipid-soluble and chain-breaking antioxidant required nutrient for humans because it is necessary for the prevention of several symptoms, including peripheral neuropathy and haemolytic anaemia. It plays a significant role in preventing or minimizing peroxidation damage in biological systems. Supplementation with vitamin E inhibits DNA damage due to free radical scavenging activity and it exerts anti-cytotoxicity and anti-genotoxicity.[50,51] Moreover, α-tocopherol showed hepatoprotective activity against cisplatin-induced oxidative stress, this effect may be attributed to down-regulations of NADPH oxidase gene expression.
Zinc (Zn) is an essential trace element with various biological effects, depending on its catalytic and structural role in an enormous number of enzymes and “Zn-finger” proteins. Zinc ions (Zn2+) control cell proliferation, differentiation and have a role in both apoptotic and necrotic cell death. Zn also has antioxidative and anti-inflammatory properties and it postulates hepatonephroprotective effect due to its antioxidant, antiapoptotic and anti-inflammatory properties against Cd-induced hepatotoxicity and reduction of metal accumulation in the organism which may lead to nephrotoxicity.[55,56]
The naturally occurring element selenium (Se) plays a major role in a wide variety of biological processes in mammals. Se acts as one of the major component due to its low molecular weight as well as to its presence within at least 25 proteins, named selenoproteins, in the form of the amino acid selenocysteine, that is incorporated during translation and is directly involved in redox catalysis. Although the function of most selenoproteins is still unknown, thioredoxin reductase, GSH peroxidases, and thyroid hormone deiodinases are well described as selenoproteins, which is involved in maintaining the cell reduction-oxidation balance and thyroid hormone metabolism. Se administration increases the antioxidant capacity of several intracellular systems. In addition, Se showed hepatoprotective effect against malathion-induced liver injury and diabetic rats.[59,60] Table 2 demonstrated the effect of micronutrients on hepatic lesions.
Table 2: Effect of micronutrients against hepatic injuryClick here to view
N-acetyl cysteine (NAC) is a derivative of the sulfur-containing amino acid cysteine and an intermediary (along with glutamic acid and glycine) in the conversion of cysteine to GSH. Oral NAC administration leads to an increase in intracellular cysteine and GSH levels. NAC is the primary antidote for acetaminophen-induced hepatotoxicity. NAC is able to inhibit genotoxicity due to reactive oxygen species (ROS), protect DNA and nuclear enzymes, and prevent the formation of carcinogen-DNA adducts. NAC succeeded in the treatment of severe hepatic injury induced by a dietary fitness supplement.
Alpha lipoic acid (ALA) influences oxidative status by scavenging ROS, regenerating endogenous anti-oxidants, repairing oxidative damage, and chelating metal ions. ALA has been proven to be a natural, yet very powerful free radical scavenger and antioxidant. ALA has a protective effect against CCl4-induced hepatotoxicity and prevents against liver fibrosis due to inhibition of transforming growth factor (TGF)/platelet-derived growth factor-stimulated hepatic stellate cells activation and ROS generation.[66-68]
L-Carnitine (CAR) is a conditionally essential nutrient synthesized endogenously from lysine and methionine in the liver, kidney and brain and it induce its effects on both fat and glucose metabolism. CAR binds to fatty acyl-CoA and regulates their transport into mitochondrial matrix for β-oxidation. L-CAR is a superoxide scavenger, antioxidant, and DNA cleavage protector. L-CAR has shown a protective effect against radiation-induced organotoxicity via induction of endogenous antioxidants. Reduction of concentration of CAR in blood and tissues is accompanied with hyperlipidemic condition. It has been well reported that hepatoprotective effect of L-CAR against CCl4-induced hepatotoxicity is due to significant increase of GSH level.
Lycopene is the red pigment of tomatoes. Lycopene concentration in human serum tends to be higher than those of all other carotenoid pigments. Lycopene showed potent anti-inflammatory effects through its action as an antioxidant and free radical scavenger, which may reduce cellular damage. It plays a crucial role in protection of cell membranes from lipid peroxidation by neutralizing hydroxyl radicals and may bind to DNA, promoting further protection beyond antioxidant activity. Lycopene demonstrated potential beneficial effects against oxidative stress. These beneficial functions are due to enhancement cellular gap junction communication, induction of phase II enzymes through activation of the antioxidant response element of transcription system, and suppression of insulin-like growth factor-1-stimulated cell proliferation. Its effects include also antiangiogenesis, inhibition of cell proliferation and induction of apoptosis. Lycopene showed potent protective effect against hepatic steatosis in knock out mice.
S-adenosyl-l-methionine (SAMe) is an endogenous agent that is a critical precursor for transmethylation and trans-sulfuration reactions. SAMe plays an important role such as a cofactor for many transmethylation reactions of amino acids, proteins, nucleotides and neurotransmitters and a vital precursor for the trans-sulfuration pathway that ultimately generates GSH. SAMe has potent activity against acetaminophen-induced hepatotoxicity as compared to NAC. SAMe reduced the cytotoxicity of other hepatotoxicants such as carbon tetrachloride, which may lead to liver fibrosis and alcohol mediated damage. SAMe was reported to protect liver against hepatic injury and fibrosis through the inhibition of oxidative stress and hepatic stellate cells formation due to activation of Smad7 (an inhibitor of TGF-beta signaling; regulator of hepatic fibrosis) messenger RNA expression.
Whey protein concentrates (WPCs) are heterogeneous compound obtained from milk after casein precipitation at pH 4.6. WPCs play an important biological role since they act as antioxidants, antihypertensive and antitumor, hypolipidemic and antiviral, antibacterial, and chelating agents. WPCs counteract oxidative stress and DNA damage in rats fed an aflatoxin-contaminated diet.[84-89] The effect of various supplements has been depicted at Table 3.
Table 3: Effect of dietary supplement against hepatotoxicity and hepatic cancerClick here to view
It can be concluded that natural bioactive compounds are promising candidate in treatment and prevention of hepatic injury as well as HCC. The effects may be due to their antioxidative properties, modulatory effects in several cytokines, and anti-genotoxic efficacy. The current article highlights on the potential mechanism of action of natural compounds against hepatotoxicity and suggests further studies for developing novel therapeutic tools in treatment of hepatic lesions.
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