Curcumin, the natural yellow-colored active principle, also called turmeric yellow, extracted from the perennial herb Curcuma longa L., has potent biological and pharmacological properties such as antioxidant, anti-inflammatory, antifungal, antibacterial, anti-ischemic, antitumor, and anticancer actions. The molecular mechanism of the hepatoprotective action of curcumin is due to its antioxidant properties and inhibitory activity against nuclear factor (NF)-κB that regulates different proinflammatory and profibrotic cytokines. Overall, scientific reports demonstrate that curcumin has high therapeutic ability for treating hepatic disorders. Here is a systematic discussion of the hepatoprotective activity of curcumin and its possible mechanisms of actions.
The liver is a multifunctional vital organ with the primary role in maintenance of body homeostasis. Among the various liver functions are plasma protein synthesis (Tacke and others 2009), production of hormones, processing dead red blood cells, detoxification (Zhao and others 2009; Yu and others 2011), and glucose and lipid metabolism (Liu and others 2012a). The crucial role of liver in maintaining human health status means that liver diseases can severely affect health status and threaten human life (Åberg and others 2009). Generally, hepatocellular carcinoma (HC, liver cancer), hepatitis, cirrhosis, and fatty liver are the most common types of liver diseases (Bellentani and others 2005). Among these diseases, liver cancer and hepatitis are the most prevalent and serious global public health problems (Sun and Karin 2008). Hepatitis or liver inflammation is caused by one of the hepatitis viruses (A, B, C, D, and E) (Hu 2008; Sun and Karin 2008). The World Health Organization (WHO) estimates that about one-third of the world's population is infected with hepatitis B virus (HBV) during a lifetime, while about 17.5% remain chronically infected. According to WHO statistics, an estimated 5% of all humans in the world are HBV carriers and a quarter of those would develop serious liver diseases such as chronic hepatitis, cirrhosis, and primary HC. It is now known that HBV infection accounts for more than 1 million deaths every year (Verhoef and others 2002; Lavanchy 2005; Perz and others 2006; Farinati and others 2007; Sun and Karin 2008).
Liver cancer (which consists mainly of HC, a malignant hepatoma) is the 5th most common cancer in men and the 7th in women (Chuan-Xing and others 2011). It also represents the 3rd cause of cancer-related deaths in the world (Vara and others 2011). According to WHO statistics, the incidence rate of HC in men is about 9 times higher than that of women, and the disease is more prevalent in one-third of all the countries than in the rest (Alsohaibani and others 2011).
Nonalcoholic fatty liver disease is another very common type of liver disease; its prevalence is more than 70% than that of type II diabetics, over 50% in obese people and nearly 100% in patients with both conditions (Morisco and others 2008). The heavy consumption of alcohol, which leads to alcoholic fatty liver disease and different types of cancer, is one of the most common preventable causes of death in the world (Stokkeland and others 2010).
Numerous medical studies have demonstrated the important role of nuclear factor-kappaB (NF-kB) signaling pathways (Sun and Karin 2008; Lee and others 2010b) and oxidative stress (Caraglia and others 2011; Tanaka and others 2013) in the pathogenesis of liver diseases and have proved the ameliorative role of dietary antioxidants (Bishayee and others 2010; Nabavi and others 2012c).
Curcumin is a bright yellow-colored phenolic compound that was initially isolated from Curcuma longa L. (turmeric) rhizomes in 1815 (Gupta and others 2013). The genus Curcuma is a member of Zingiberaceae family, growing in India, Southeast Asia, and other tropical areas (Martin and others 2012).
The yellow color of turmeric, with its principal component curcumin, has a long history in traditional medicine and as a food ingredient (Benzie and Wachtel-Galor 2011; Martin and others 2012). Three different analogs of curcumin have been isolated from C. longa L. rhizome, diferuloylmethane, demethoxycurcumin, and bisdemethoxycurcumin (Figure 1).
Current commercial curcumin preparations consist of diferuloylmethane (77%), demethoxycurcumin (18%), and bisdemethoxycurcumin (5%) that are all hydrophobic substances and usually dissolved in dimethylsulfoxide, organic solvents, or oils (Shehzad and Lee 2010). The curcumin UV-Vis absorption spectrum shows an absorption maximum approximately at λ = 420 nm (Priyadarsini 2009). In acidic solution, the color of curcumin changes from yellow to deep red (Lin and Lin-Shiau 2009).
Nowadays, many attentions have been paid to clinical utilization of curcumin (Hatcher and others 2008). More than 84 clinical studies, including randomized blind placebo-controlled, nonrandomized phase II/III trials, and so on (www.ClinicalTrials.gov), are investigating the effects of curcumin on human disorders (for example, mild cognitive impairment, asthma, Alzheimer's disease, dermatitis, adenomatous polyposis, multiple myeloma, type 1 and 2 diabetes, schizophrenia, irritable bowel syndrome, prostate cancer, pancreatic cancer, colorectal cancer, head and neck cancer, glioblastoma, myelodysplastic syndrome, knee osteoarthritis, rheumatoid arthritis, major depressive disorder, bipolar disorder, ulcerative colitis, osteosarcoma, Leber's hereditary optic neuropathy, chronic obstructive pulmonary disease, chemotherapy-induced mucositis, abdominal aortic aneurysm, proteinuric chronic kidney disease, nonsmall cell lung cancer, aberrant crypt foci in the human colon, kidney allografts, hyperprolactinoma, oral lichen planus, diabetes Crohn's disease, chronic psoriasis vulgaris, fibromyalgia, and cystic fibrosis) when given alone or conjunction with other drugs or nutriceuticals. Early studies evaluated safety and pharmacokinetics of curcumin in normal and/or patient population. While other studies evaluate efficacy of curcumin associated with aforementioned aspects (Goel and others 2008).
Following oral administration, curcumin is known to be metabolically converted to curcumin sulfate and curcumin glucuronide (Basnet and Skalko-Basnet 2011) (Figure 2), while intraperitoneal administration leads to the formation of hexahydrocurcuminol, hexahydrocurcumin, and tetrahydrocurcumin (Marczylo and others 2009) (Figure 3).
The chemical structure of curcumin (1, 7-bis [4-hydroxy-3-methoxyphenyl]-1,6-heptadiene-3,5-dione, Figure 1) reveals its various functional groups. The 2 aromatic phenol rings (rings A and B) are connected by 2 sets of α, β-unsaturated carbonyl groups (Pullakhandam and others 2009) that are a good Michael acceptor and can react with glutathione and other nucleophiles (Scapagnini and others 2011). The 2 aryl methoxyl groups at the ortho position, the hydroxyl moiety as well as the conjugated β-diketone moieties of curcumin, which are conjugated, are other important structural features (Nabavi and others 2012a) (Figure 1).
The different methoxy substitutions in the chemical structure of diferuloylmethane, demethoxycurcumin, and bisdemethoxycurcumin (Figure 1) are responsible for a range of differential biological and pharmacological activities of these compounds (Anand and others 2008). There are, however, negligible systematic studies showing the correlation between the physicochemical and molecular characteristics of these compounds with their biological and/or pharmacological activities. Some scientific reports have demonstrated that diferuloylmethane displays better antioxidant activity than demethoxycurcumin and bisdemethoxycurcumin (Somparn and others 2007), while other reports have shown demethoxycurcumin to have better antioxidant effect than bisdemethoxycurcumin (Somparn and others 2007; Anand and others 2008). These observations suggest that the o-methoxy substitutions (OMe) are responsible for the differential antioxidant activities of diferuloylmethane, demethoxycurcumin, and bisdemethoxycurcumin (Singh and others 2011). It has also been suggested that hydrogen-bonding interaction between the phenol rings (hydroxyy and o-methoxy groups) in diferuloylmethane significantly affects the energy of O–H bond and hydrogen-donating potential, leading to better antioxidant action (Anand and others 2008). Transition metal chelation property is known as another antioxidant mechanism of curcumin, which is attributed to the diketone and the o-methoxy phenol moieties (Anand and others 2008).
The heme oxygenase-1 and NF-kB suppression by diferuloylmethane, demethoxycurcumin, and bisdemethoxycurcumin has been suggested to be attributed to α,β-unsaturated diketone structural moieties, which can act as a Michael reaction acceptor (Jeong and others 2009; Rajasekaran 2011).
Tetrahydrocurcumin is also known to be produced after intraperitoneal administration of curcumin through hydrogenation of the heptadiene moiety. When compared with curcumin, this metabolite displays a significantly higher antioxidant activity and reduced antitumor and anti-inflammatory abilities (Somparn and others 2007; Itokawa and others 2008; Teiten and others 2010).
It is further reported that when the o-methoxy phenol groups do not occur in conjugation with the β-diketone moiety, as in the case of tetrahydrocurcumin, the antioxidant activity is significantly increased (Anand and others 2008). This reaction leads to oxidative cleavage of the C-C bond at the active methylene carbon of the β-diketone moiety, leading to smaller o-methoxy phenol derivatives with better antioxidant potential (Leu and Maa 2002). Other reports also suggest that the α, β-unsaturated diketone moiety, in conjugation with phenolic rings, has a crucial role in NF-kB activity and ROS-generating activity of curcuminoids (Sandur and others 2007).
Curcumin is able to bind and inhibit various enzymes, metals, proteins such as albumin, growth factor receptors, and other important biomolecules (Goel and others 2008). Curcumin also demonstrates anti-inflammatory action and inhibitory effects against reactive oxygen-generating enzymes such as xanthine dehydrogenase/oxidase, lipoxygenase/cyclooxygenase, and inducible nitric oxide synthase (Lin 2007). Potent heme oxygenase-1-inducing (Chen and others 2012) and potent protein kinase C (PKC) (Watson and others 2010), EGF-receptor tyrosine kinase (Aggarwal and Sung 2009), and IκB kinase β (IKKβ) kinase inhibitory actions (Kim and others 2011) of curcumin have also been previously reported for curcumin. Furthermore, potent inhibitory activities of curcumin on NF-kB activation and expressions of some oncogenes such as Akt, CDKs, NIK, MAPKs, ERK, ELK, PI3K, c-jun, c-fos, c-myc, and inducible nitric oxide synthase have been reported (Das and others 2010). It is well known that the major upstream molecular targets of curcumin are EGFR tyrosine kinase, PKC, and mTOR, while downstream molecular targets include CDKs, FAS, c-jun, c-fos, c-myc, and inducible nitric oxide synthase (Lin 2007). In the target cells, curcumin suppresses tumor development by blocking some key signal transduction pathways (Shehzad and others 2010). Compounds like trifluoroacetic acid (oxidant tumor promoter) are known to activate PKC through reaction with zinc thiolates of the regulatory domain (Lin 2007). Likewise, the oxidized form of curcumin induces oxidation to vicinal thiols in the catalytic domain leading to activation of PKC (Das and others 2010). Recently, it has also been reported that ubiquitin proteasome-mediated degradation plays a crucial role in some cellular regulatory processes such as cell cycle, differentiation, proliferation, and apoptosis (Adams 2004). Moreover, curcumin induces apoptosis in cells via ubiquitin-proteasome pathway impairment and blocking the loss of misfolded N-CoR protein (Ng and others 2011).
Source and Bioavailability
C. longa, the main source of curcumin, is a short-stemmed rhizomatous perennial plant of the Zingiberaceae family (Figure 4) (Hayakawa and others 2011). The plant is widely cultivated in different countries of Asia such as India and China (Hayakawa and others 2011). In traditional medicine, C. longa has been used for mitigation of rheumatism and inflammatory and ulcerative diseases (Nabavi and others 2012b). The bright orange-colored rhizome of C. longa is commonly used as a spice in Asian and many other countries (Chaturvedi 2009). The main coloring constituent of the C. longa rhizome, “curcumin,” has been isolated and its chemical structure determined in 1910 (Agrawal and Mishra 2009).
The poor bioavailability of curcumin limits the translation into clinically relevant strategies (Bar-Sela and others 2010). Low absorption, rapid metabolism, and quick elimination are known as the main complications that limit its bioavailability and have prompted the researchers to investigate not only the biofunctional and therapeutic properties in clinical studies, but also to develop new delivery systems (Bar-Sela and others 2010; Mythri and others 2012). Curcumin is poorly dissolved in water (Kakran and others 2012). Furthermore, UV light can degrade curcumin solution and therefore photochemical degradation is another limitation of its uses (Priyadarsini 2009). There are several methods for increasing its bioavailability, such as using adjuvants such as piperine, nanoparticles, liposomal curcumin, complexes of curcumin with phospholipids, and structural analog of curcumin (Mohanty and Sahoo 2010; Yadav and others 2012).
The FAO and WHO Expert Committee on Food Additives in 1996 reported that the acceptable daily intake (ADI) of curcumin is up to 3 mg/kg body weight. It is well known that curcumin is a natural product with a long history of consumption in the human diet, but there appear to be few scientific studies on its toxicity to both animals and humans, especially at high doses (Rivera-Espinoza and Muriel 2009). Previous studies showed that high concentration of curcumin causes chromosome aberrations, astrocyte cell death, teratogenic effect, embryo-, and reproductive toxicities (Ganiger and others 2007; Wu and others 2007; Burgos-Morón and others 2010; Romero-Hernández and others 2013). Rasyid and Lelo (1999) found that curcumin should not recommend for gallstones patients inasmuch as it induces contraction of human gallbladder.
In 2010, the European Food Safety Authority (EFSA) concluded that the literature data support an ADI of 3 mg/kg bw/day (EFSA Panel on Food Additives and Nutrient Sources Added to Food 2010). More systematic toxicity studies are needed to fully address the safety of curcumin (Rivera-Espinoza and Muriel 2009).
Biological and Pharmacological Actions
Several reports have documented the potent antioxidant capacity of curcumin whereby mitigation of lipid peroxidation and oxidative stress in several tissues were demonstrated (Nabavi and others 2011a, 2012b). These protective actions are due to the curcumin ability to modify antioxidant enzymes such as superoxide dismutase, catalase, and glutathione peroxidase (Nabavi and others 2011a, 2012b). In this context, curcumin has been shown to be more active than vitamin E (Shishodia and others 2006). Curcumin is also known as a Michael acceptor that reacts with the thiol group of glutathione and thioredoxin 1 (Adams and others 2005). It is well known that the phenolic hydroxyl groups play an important role in the antioxidant activity of curcumin (Feng and Liu 2009). The role of the β-diketone moiety in the antioxidant action of curcumin has also been reported in studies regarding dimethyltetrahydrocurcumin (Anand and others 2008). Furthermore, it has been reported that the ortho alkoxy group plays a significant role in the antioxidant activity of curcumin (Amorati and others 2009). Under in vivo conditions, the position of the hydroxyl group having a crucial role in the improvement of antioxidant activity of curcuminoids (Somparn and others 2007). As evidenced from tetrahydrocurcumin, a reduction of the C-C of the C7 linker apparently does not have any effect on antioxidant activity (Rajasekaran 2011).
The anti-inflammatory effect of curcumin is partly mediated through inhibition of IkB kinase activity leading to suppression of NF-kB activation. It has been shown that the saturation of the alkene and the decrease of carbonyl functions lead to diminish the anti-inflammatory effect (Pan and others 2000; Anand and others 2008). According to Nurfina and others (1997), the presence of a 4-hydroxyphenyl moiety is necessary for the anti-inflammatory activity of curcumin. They also found that the anti-inflammatory effect could be enhanced if additional alkyl or alkoxy groups occur at the 3- and 5-positions on the phenyl ring (Hong and others 2004). It has also been shown that acylation and alkylation of the phenolic hydroxyl group of curcumin severely reduce its anti-inflammatory activity (Anand and others 2008). Hong and others (2004) further demonstrated that the presence of phenolic hydroxy groups is necessary for the COX-1 inhibitory effect of curcumin. To date, several scientific reports have documented the anticancer effects of curcumin in various experimental models (Duvoix and others 2005; Johnson and Mukhtar 2007; Wilken and others 2011; Yan and others 2012). These effects include blocking of cell transformation (Bakhshi and others 2008), tumor promotion (Dance-Barnes and others 2009), tumor initiation (Huang and others 1992), angiogenesis (Kunnumakkara and others 2007), invasion (Kim Im and others 2008), and metastasis (Kunnumakkara and others 2008). Curcumin potential in suppressing carcinogenesis in the forestomach, colon, liver, and skin (Sethi and others 2009) has also been established. Moreover, the antiproliferative effects of curcumin against different types of tumor cells, such as colon carcinoma (Nautiyal and others 2010), B-cell and T-cell leukemia (Angelo and Kurzrock 2009), epidermoid carcinoma (Chan and others 2003), and several types of breast carcinoma cells (Liu and others 2009) have been reported by various authors. Structurally, the anticancer effect of curcumin is evident from its classical Michael acceptors, which are associated with reduction of intracellular glutathione (GSH) in human colon cancer cells (Adams and others 2005; Anand and others 2008). The presence of hydroxyphenyl groups further contributes to the chemoprotective action of curcumin, partly due to its ability in inducing phase II detoxification enzymes (Pullakhandam and others 2009).
Curcumin has a potent effect against several types of viruses such as human immunodeficiency virus-1 (Chai and others 2005), herpes simplex virus-1 (Kutluay and others 2008), hepatitis C virus (Kim and others 2010), influenza virus (Chen and others 2010), human papillomaviruses (Prusty and Das 2004), and so on. The treatment with curcumin significantly prevents lung and kidney injuries in different experimental models (Gunaydın and others 2012; Liu and others 2012b; Nabavi and others 2012a; Ueki and others 2012). It has also been reported that consumption of curcumin incurs a protective role against atherosclerosis (Shin and others 2011) and myocardial infarction (Wang and others 2012), an effect widely believed to be mediated through inhibition of proliferation of vascular smooth muscle cells (Chen and Huang 2009) and peripheral blood mononuclear cells (atherosclerosis) (Ahmed and others 2011), low-density lipoprotein oxidation (Kang and Chen 2009), oxidative stress in cardiac tissues (Nabavi and others 2011b), and platelet aggregation (myocardial infarction) (Shah and others 1999).
The antirheumatic and antiarthritic effects of curcumin could also be explained by its ability to modify COX2, tumor necrosis factor alpha (TNF-α), and other proinflammatory protein targets (Khanna and others 2007). Curcumin has also been shown to suppress allergic encephalomyelitis by blocking interleukin-12-signaling in T cells (Natarajan and Bright 2002). In experimental models of Alzheimer's disease, treatment with curcumin has been shown to ameliorate oxidative stress (Lim and others 2001), cognitive impairment (Baum and others 2008), and amyloid accumulation in the brain tissues (Yang and others 2005). Furthermore, treatment with curcumin significantly mitigates inflammatory bowel disease (Holt and others 2005) and diarrhea (Conteas and others 2009). It has also been reported that curcumin can modify cystic fibrosis defects by preventing mutations in the trans-membrane conductance regulator gene (Egan and others 2004).
The abilities of curcumin in the mitigation of several skin diseases such as psoriasis (Kurd and others 2008), scleroderma (Thangapazham and others 2007), and skin carcinogenesis (Limtrakul and others 1997) have previously been reported. Also, it is well known that curcumin accelerates wound-healing via inhibition of NF-κB (Sidhu and others 2002). Quenching of free radicals (Thangapazham and others 2007), inhibition of NF-κB (Sidhu and others 2002), transforming growth factor (TGF)-β (Pratsinis and others 2004), and mitogen-activated protein kinase pathway (Chun and others 2003) have been shown to have an important role for the skin protection effect of curcumin. Other studies suggest that curcumin ability in modifying phase II detoxification enzymes has a crucial role in detoxification reactions and oxidative stress (Anand and others 2008).
Curcumin improves life and health span via modulation of expression of different aging-related genes such as mth, thor, InR, and JNK in Drosophila melanogaster (Lee and others 2010a). The protective role of curcumin against chronic cerebral ischemia is due to its ability in the modification of the protein levels of UCP2, oxidative stress (Gao and others 2012), and expression of α-synuclein (Yu and others 2012). Curcumin mitigates gastric ulcer by stimulating angiogenesis and collagen fiber restitution and modification of matrix metalloproteinase (MMP)-2, TGF-β, and vascular endothelial growth factor (VEGF) expression (Sharma and others 2012). In diabetes, administration of curcumin mitigates renal dysfunctions via inhibition of p300 and NF-κB (Pan and others 2013). In alloxan-induced diabetic models, curcumin has been shown to decrease blood sugar, hemoglobin, and glycosylated hemoglobin levels (Arun and Nalini 2002). Furthermore, modification of plasma concentrations and abnormalities in the excretion of albumin, creatinine, urea, and inorganic phosphorus have been reported for curcumin (Suresh Babu and Srinivasan 1995). The ability of curcumin in the mitigation of retinal oxidative stress and inflammation in diabetes has also been reported (Kowluru and Kanwar 2007). Behavioral and biochemical studies further showed that curcumin ameliorates diabetic encephalopathy in experimental rats (Kuhad and Chopra 2007).
HBV is a small DNA member of the genus Orthohepadnavirus (Hepadnaviridae family) (Glebe 2007). HBV causes liver infections that lead to different hepatic disorders such as hepatitis, cirrhosis, and HC (Jazayeri and others 2009; Liaw and Chu 2009). The best clinical protocol for the management of hepatitis B viral infection is through the use of nucleotide/nucleoside analog (Fung and others 2011). These drugs suppress HBV via modification of polymerase/reverse-transcriptase activity (Balsano and Alisi 2008). It has been, however, reported that long-term treatment of polymerase inhibitors increases the risk of escape mutants emerging (Zoulim 2004b). Therefore, the search for finding of a better anti-HBV therapy has been intensified in recent years (Zoulim 2004a). During hepatitis B viral infection, the metabolic regulator PGC-1α coactivates the transcription of HBV via the forkhead transcription factor FOXO1 and the nuclear receptor HNF4α (Ganem and Prince 2004; Quasdorff and others 2008; Quasdorff and Protzer 2010). It has been reported that repression of PGC-1α leads to downregulation of HBV expression under the fed and starvation states (Shlomai and others 2006). Targeting PGC-1α is therefore a viable strategy for anti-HBV therapy (Ganem and Prince 2004). A recent report shows that curcumin downregulates PGC-1α and significantly suppresses HBV gene expression (Rechtman and others 2010). Furthermore, HBV has susceptible potential to manipulations of crucial molecular metabolic pathways of the liver such as gluconeogenesis (Duclos-Vall and others 1998). It has been further suggested that the combination of curcumin with nucleotide/nucleoside analog can synergistically suppress HBV replication and the risk of escape mutants emerging may be prevented (Rechtman and others 2010).
The hepatitis C virus with positive-sense single-stranded 9.6 kb RNA genome is a member of the Flaviviridae family (De Francesco 1999), which causes chronic hepatitis, fibrosis (Poynard and others 1997), cirrhosis, and HC (Degos and others 2000). Current estimates indicate that hepatitis C viral infection affects more than 170 million people all over the world (Alavian and others 2009).
It is well known that the combination of pegylated interferon-α and ribavirin is the best method for treating hepatitis C viral infection (Muir and others 2004). It has been reported, however, that nearly one-half of infected patients do not show any positive response to exogenous pegylated interferon-α (Mathew and others 2006). Therefore, studies for finding novel treatment protocols with lower side effects and more efficacious anti-hepatitis C viral infection are urgently needed.
A recent report shows that curcumin inhibits hepatitis C virus replication by suppressing PI3K/Akt-SREBP-1 pathway (Kim and others 2010). It can also be concluded that curcumin may decrease the risk of hepatitis C virus-related HC through its protective role against hepatitis C virus infection (Kubo and others 2002; Kim and others 2010).
Alcoholic liver disease
According to the WHO, alcohol-related death and disability accounted for nearly 4% of the total global burden of disease in the year 2000. In the U.S.A., one of the most important preventable causes of death is the excessive consumption of alcohol, which is associated with multiple adverse health consequences, such as acute and chronic liver damages and different types of cancers (Mokdad and others 2004; Paula and others 2010; Chen and others 2011; Jemal and others 2012; Simard and others 2012). Hence, a close correlation between alcohol consumption and alcoholic liver disease has been established (Hart and others 2010). However, liver cirrhosis occurred in few groups of heavy alcohol drinkers and its incidence risk rises with increasing consumption over 30 g alcohol per day (Bellentani and others 1997; Lucey and others 2009). According to some statistical reports, the incidence rate of cirrhosis is up to 5.7% in people consuming 120 g alcohol daily (heavy alcohol drinkers)(Lucey and others 2009). Alcohol consumption, just for a few days, leads to liver steatosis (commonly called fatty liver) (Adachi and Brenner 2005; Suter and Tremblay 2005), which is defined as the status in which hepatocytes contain macrovesicular droplets of triglycerides (Lucey and others 2009). Fatty liver can be a temporary or a long-term condition, which is not harmful itself but may induce some other disease conditions. Left untreated, it can contribute to the development of hepatic fibrosis (Jepsen and others 2009; Bataller and others 2011; Naveau and others 2013) and cirrhosis. Obviously, this disorder can be mitigated by alcohol avoidance (Lucey and others 2009).
The protective action of curcumin against experimental models of alcoholic liver diseases has been reported previously (Nanji and others 1999). It was shown that treatment with dietary curcumin reduced fatty liver, necrosis, and inflammation. Curcumin is also known to inhibit oxidative stress and lipid peroxidation, activation of NF-kB, and the expression of TNF-α, IL-12, MCP-1, MIP-2, COX-2, and iNOS (Nanji and others 1999). Animal studies have further shown that curcumin decreases the ethanol-induced increase in malondialdehyde, decreases the levels of lactate dehydrogenase (LDH) and aspartate aminotransferase (AST), and increases the GSH levels (Bao and others 2010). Although the protective role of NF-kB activation modulator against alcoholic liver injury has been documented previously (Nanji and others 2003), clinical studies on the protective role of curcumin against alcohol-induced liver injury are limited and therefore required for a comprehensive assessment of curcumin's overall therapeutic potential in this field.
Nonalcoholic fatty liver disease
Pathological studies have revealed that nonalcoholic fatty liver diseases were similar to alcoholic liver injury but they occurred in patients who did not consume alcohol (Angulo 2002; Clark and Diehl 2003). Nonalcoholic fatty liver diseases are the most important liver diseases; they affect more than 20% of people in the U.S.A. (Clark and Diehl 2003; Kim and Younossi 2008). Nonalcoholic fatty liver diseases consist of a variety of liver pathologies that range from simple steatosis to steatohepatitis, fibrosis, and cirrhosis (Brea and others 2005). Nonalcoholic fatty liver disease is closely correlated with obesity, overweight, metabolic syndrome, and type 2 diabetes in adult and pediatric individuals (Fabbrini and others 2009; Ortiz-Lopez and others 2012). According to some histological studies, nonalcoholic fatty liver disease causes a variety of changes, including macrovesicular steatosis (Tiniakos and others 2010), lobular inflammatory infiltrate, hepatocellular ballooning (Brunt 2010), perisinusoidal fibrosis (Brunt 2012), and Mallory's hyaline (Puri and Sanyal 2012). It has been reported that intraperitoneal administrations of curcumin mitigates fibrosis and modifies intrahepatic gene expression of monocyte chemoattractant protein-1, CD11b, procollagen type I, NF-κB, ICAM-1, COX-2, TNF-α, and protein levels of α-smooth muscle-actin (Leclercq and others 2004; Vizzutti and others 2009). Curcumin also inhibits oxidative stress via modification of mitochondrial reactive oxygen species (Ramirez-Tortosa and others 2009) and 8-OH deoxyguanosine levels (Vizzutti and others 2009). Moreover, curcumin inhibits reactive oxygen species production in myofibroblastic hepatic stellate cells and modifies secretion of tissue inhibitor of metalloprotease-1 (Vizzutti and others 2009). Curcumin is also known to modify the abnormal increase in the level of aminotransferases (Ramirez-Tortosa and others 2009). Histologically, curcumin has been demonstrated to mitigate steatosis and necro-inflammation in the hepatic tissues. In conclusion, curcumin effectively mitigates nonalcoholic fatty liver diseases via its antioxidant and anti-inflammatory actions (Vizzutti and others 2009).
Hepatotoxicity is known as a common side effect of over 1000 drugs, but its prevalence for many drugs is lower than 1 case in 10000 (Kaplowitz 2005; Navarro and Senior 2006). According to some U.S.A. statistical data, drug-related hepatotoxicity accounts for 50% of liver injuries including both chronic and acute liver diseases (Lee 2003). In most cases, cessation of the drug and consequent supportive care are the only effective solutions for the treatment of drug-induced hepatotoxicity (Navarro and Senior 2006). For example, in the U.S.A., suicide attempts account for over two-thirds of acetaminophen-related liver injury, whereas accidental overdose accounts for only one-third of the cases. Using N-acetylcysteine after an intentional or unintentional overdose of acetaminophen (Woodhead and others 2012) is the most known exception for the aforementioned intervention approach.
Drug-induced hepatotoxicity is one of the most important reasons that is cited for withdrawing drugs from the market by the U.S. Food and Drug Administration (FDA) (Lee 2003). Drugs or their metabolites can cause direct cellular damage or stimulate immune response that may lead to apoptosis or necrosis in hepatocytes (Liu and Kaplowitz 2002; Kaplowitz 2004). General mechanisms, which are involved in drug-induced hepatitis, include reactive metabolite formations, oxidative stress, GSH depletion, and protein alkylation (Grattagliano and others 2009). These processes directly influence the normal function of several organelle including mitochondria, the cytoskeleton, endoplasmic reticulum, microtubules, and/or the nucleus (Kaplowitz 2004; Gunawan and Kaplowitz 2007). Also, they can change cellular organelle functions through changes in the activation or inhibition of signaling kinases, transcription factors, and protein expression (Kaplowitz 2004; Gunawan and Kaplowitz 2007). These intracellular stresses were observed to be associated with deregulation of Jun-N-terminal kinase-1 (Nakagawa and others 2008), B-cell lymphoma-2 protein family (Bmf, Bim, Bax, and Bak) (Kaplowitz 2004), and c/EBP homologous protein-10 (Pessayre and others 2010). It has been further reported that the activation of B-cell lymphoma-2 protein family members causes massive mitochondrial injury through formation of pores in the outer mitochondrial membrane and triggers chromatin condensation and DNA fragmentation (Mohamad and others 2005). Moreover, mitochondrial dysfunction reduces energy production and causes release of nucleases through change in membrane potential collapse, which is caused by changing membrane permeability (Grattagliano and others 2009). Reactive metabolites can also stimulate immune response and cause immune-mediated injury by either covalently binding with liver proteins, such as cytochrome P450 enzymes, or involving hapten-like action (Wu and others 2010; Vogel and Manns 2012). Although the exact mechanism of immune-mediated liver injury is not fully understood, it is assumed that FasL and the perforin/granzyme B pathways have a crucial role in drug-induced immune-mediated hepatocyte apoptosis (Warrington 2012).
The ameliorative effect of curcumin and its derivatives against liver injury induced by several drugs, such as paracetamol (Girish and others 2009), chloroquine (Dattani and others 2010), methotrexate (Hemeida and Mohafez 2008), erythromycin estolate (Pari and Murugan 2004), isoniazid, rifampicin, and pyrazinamide (Adhvaryu and others 2007), has been reported. Antioxidant ability of curcumin and its derivatives is shown to be the main protective mechanism against drug-induced liver damages (Negi and others 2008). Curcumin, as a strong inhibitor of cytochrome P450 (Thapliyal and Maru 2001), can normalize antioxidant enzymes and nonenzymatic antioxidant compounds such as GSH (Oetari and others 1996). Bulku and others (2012) also demonstrated that curcumin ameliorates acetaminophen-induced liver damage through normalization of proapoptotic (Bax, caspase-3) and antiapoptotic signaling pathways the curcumin chemopreventive potential is further shown by it capacity to inhibit COX-2 and iNOS expression through NF-kB pathways that are considered another possible ameliorative mechanism against drug-induced liver damage (Puri and Sanyal 2012).
Numerous annual reports demonstrate that HC is responsible for more than 696000 deaths all over the world, and accounts for about 90% of all cases of liver cancer and is the 3rd most common cause of cancer mortality (9.2%) (Ferlay and others 2010). Despite many approaches for treating liver cancer, the prognosis remains poor. According to WHO statistics, the incidence rate of HC in men is higher than in women. This suggests that gender and gender-related factors are important factors in HC (El-Serag 2004). Although the reason of the high HC incidence is unclear, there are systematic differences in the microRNA expression patterns of liver tissues in men and women (Ji and others 2009). A recent report on the inhibitory activity of estrogen on interleukin-6 induction in Kupfer cells may have crucial role in the observed gender difference of HC incidence (Wands 2007).
Liver cancer is also commonly associated with viral infections, as a high incidence is reported in hepatitis B and C sufferers (Benvegnù and others 2006). Although surgical methods are the most effective procedures for treating HC, only 20% of patients are eligible to go through this scheme (Shi and others 2007). Treatment via interferon α and transcatheter arterial chemoembolization have a key role in prolonging the survival time of patients with HC (Sun and others 2006; Peng and others 2009).
Many studies demonstrate the overexpression of Bcl-2 members (Chang and Xu 2000) and inhibitors of apoptosis proteins (IAPs) occurring during HC (Augello and others 2009). It is well known that IAPs (c-IAP-1, c-IAP-2, XIAP, NAIP surviving, and livin-α) and X-linked inhibitor-of-apoptosis protein (XIAP) through inhibiting effector caspases can inhibit cell death (Deveraux and Reed 1999; Vucic and others 2000; Kasof and Gomes 2001; Notarbartolo and others 2005; Augello and others 2009). Moreover, XIAP X-chromosome-linked inhibitor of apoptosis proteins (XIAP) can initiate proteasome degradation of caspases and 2nd mitochondria-derived activator of caspases (Smac) (MacFarlane and others 2002). Recently, overexpression of Smac in HC tumors is used as an effective strategy for cancer treatment (Zhao and others 2006) because Smac sensitizes tumor cells to chemotherapeutic drugs (Zhao and others 2006). It is further known that NF-kB upregulates the expression level of XIAP and other IAPs as well as other NF-kB target genes in HC tumor cells (Wang and others 1998; Mitsiades and others 2002). Besides NF-kB, HC cells can control cell proliferation and growth through expression of other transcription factors, such as AP-1 and STATs (Liu and others 2002). Curcumin is well known for its potent NF-kB inhibitory activity (Chan 1995, Darvesh and others 2012). It can also interact with AP-1 and STATs (Notarbartolo and others 2005). Therefore, curcumin influences NF-kB, AP-1, and STATs, apoptotic mechanisms in human HC (Aggarwal and others 2003; Notarbartolo and others 2005). Recent evidence further shows that p38 activation-induced FasL expression signaling in human HC Huh7 cells has a crucial role in apoptosis-inducing activity of curcumin (Wang and others 2013).
MicroRNAs (miRNAs) deregulation is another mechanism that is involved in human HC (Ladeiro and others 2008; Iorio and Croce 2009). miRNAs are noncoding small RNAs composed of about 22 nucleotides that function in the transcriptional and posttranscriptional regulation of target genes (He and Hannon 2004; Chekulaeva and Filipowicz 2009). Most of the mammalian mRNAs are conserved targets of about 1000 miRNAs that are encoded by the human genome (John and others 2004; Chang and Mendell 2007; Guo and others 2010). Previous studies have shown that miRNAs are implicated in different biological processes including development, apoptosis, differentiation stress response, proliferation, and so on (Croce and Calin 2005). Over the past several years, numerous reports have shown that miRNAs levels are deregulated in most of human tumors (Calin and Croce 2006; Deng and others 2008; Garzon and others 2009). Ladeiro and others (2008) reported that dysregulation of miR-224 miR-200c, miR-200, miR-21, miR-224, miR-10b, and miR-222 has important roles in initiation or malignancy of hepatocellular carcinoma (HCC) tumors. Another study showed that HC caused a decrease in miR-199a/b-3p level and there was a close correlation between miR-199a/b-3p level and survival of patients (Hou and others 2011). As a function of microRNA, miR-199a/b-3p targets tumor-promoting PAK4 and represses tumor growth through suppressing the PAK4/Raf/MEK/ERK pathway (Hou and others 2011). Other studies report significant elevations of E2F1 and oncoproteins Bcl-2 level in human HC (Ladu and others 2008; Yang and others 2011). Curcumin administration showed a significant decrease in E2F1 and Bcl-2 protein levels (Li and others 2007). Hassan and Al-Olayan (2012) also showed that curcumin administration can normalize the expression levels of miR-199 and miR-200 families. Curcumin not only influences the expression of miR-21 and miR-34a, but also upregulates tumor suppressor let-7a miRNA (Subramaniam and others 2012).
Liver cancer promotes neovascularization and angiogenesis in HC tumors (Semela and Dufour 2004) that are regulated by different molecular signaling pathways including extracellular signal-regulated kinase 1/2 and serine/threonine kinase AKT (Schmitz and others 2008). Extracellular signal-regulated kinase is a mitogen-activated PKC cascade that is involved in different cell cycle processes including growth and proliferation (Zhang and Liu 2002; Wada and Penninger 2004). It has been reported that extracellular signal-regulated kinase is activated by VEGF (Rousseau and others 1997). The AKT pathways also have crucial role in cell cycles (Liang and Slingerland 2003). On the basis of previous reports, it has been suggested that elevation of phosphor extracellular signal-regulated kinase 1/2 and AKT expression levels are associated with aggressive tumor behaviors in HC (Schmitz and others 2008). Curcumin administration can significantly repress different angiogenic biomarkers such as VEGF, and cyclooxygenase-2 (COX-2) expression (Yoysungnoen and others 2006; Binion and others 2008). It has recently been demonstrated that PI-3/AKT, MAP kinase/ERK, and signal transducer and activator of transcription 3 (STAT3) pathways influence COX-2 and VEGF-stimulating pathways (Niu and others 2002; Kwon and others 2003; St-Germain and others 2004; Lo and others 2010). Moreover, it has been reported that the repression effect of curcumin on STAT3 (Yoysungnoen and others 2006) and hypoxia-inducible factor-1α expression in human HC leads to reduced tumor angiogenesis and progression (Bae and others 2006). Hence, the above-mentioned pathways are possible tumor angiogenesis suppression mechanism of curcumin (Bae and others 2006). Another possible antiproliferative mechanism of curcumin against HC is through induction of endoplasmic reticulum stress and mitochondrial dysfunction (Cheng and others 2010). Lin and others (1998) showed that the suppression effect of curcumin on MMP-9 secretion is its anti-invasion mechanism in HC SK-Hep-1 cells.
Primary biliary cirrhosis is an autoimmune chronic cholestatic liver inflammation that slowly blocks the flow of bile and subsequently causes liver scarring, fibrosis, and cirrhosis (Dienes and others 1997; Leuschner 2003; Kaplan and Gershwin 2005). According to the histopathological studies, primary biliary cirrhosis causes nonsuppurative interlobular bile duct destruction (Talwalkar and Lindor 2003). It is well known that immunological and genetic factors have an important role in initiation and progression of this disease (Tanaka and others 2001). The sex ratio of primary biliary cirrhosis shows that affected patients are commonly middle-aged women with an asymptomatic increase in serum hepatic factors (sex ratio is 9 : 1, female : male) (Invernizzi and others 2004; Danielsson and others 2005). Fatigue, fatty deposits under the skin, itching, jaundice, and xanthelasma are the most commonly symptoms of primary biliary cirrhosis (Kaplan and Gershwin 2005; Sargent 2008). Ursodeoxycholic acid is the most common medical treatment of primary biliary cirrhosis, and it is approved by U.S. Food and Drug Administration (Lindor 2007).
TGF-β is an important profibrogenic cytokine in the development of fibrosis (Yao and others 2012). TGF-β stimulates the production of extracellular matrix and blocks its removing procedures (Branton and Kopp 1999). It is well known that TGF-β has a crucial role in activation of trans-differentiation of hepatic stellate cells to myofibroblasts in liver fibrogenesis (Shen and others 2003). Curcumin inhibits the profibrotic role of TGF-β and prevent fibrosis in fibrotic lung and kidney disorder (Gaedeke and others 2004; Reyes-Gordillo and others 2008; Punithavathi and others 2009).
It has also been reported that curcumin ameliorates cirrhosis induced by bile duct ligation through downregulation of TGF-β and inhibition of oxidative stress (Reyes-Gordillo and others 2008). Numerous reports suggest the role of TGF-β in the expression of different profibrotic genes (Gaedeke and others 2004; Leask and Abraham 2004). Curcumin inhibits upregulation of TGF-β mRNA and TGF-β protein expressions in hepatic tissues of bile duct-ligated rats (Reyes-Gordillo and others 2008). The preventive role of curcumin against fibrosis induced by biliary cirrhosis could be attributed to its antioxidant action and its downregulation effects on NF-kB and TGF-β (Leask and Abraham 2004; Dohmen and others 2004; Salunga and others 2007; Reyes-Gordillo and others 2008).
Primary sclerosing cholangitis
Primary sclerosing cholangitis is a chronic cholestatic liver disease that causes inflammation, fibrosis, scarring, and destruction of the bile ducts at intrahepatic and extrahepatic levels (Cullen and Chapman 2003; Harrison and others 2005). The disease is a progressive immune-mediated disorder that culminates in cirrhosis, hepatic decompensation, and portal hypertension (Chapman and others 2010). About 70% of primary sclerosing cholangitis patients are young and middle-aged men (Mendes and Lindor 2010). More than 87% of primary sclerosing cholangitis patients are shown to have ulcerative colitis and 13% of them have Crohn's disease (Lee and Kaplan 2002). This pathology is often associated with inflammatory bowel disease (Jørgensen and others 2012). Other studies indicate that some of the primary sclerosing cholangitis patients have autoimmune disorders, chronic pancreatitis, and sarcoidosis (Saich and Chapman 2008; Kamisawa and others 2009; Bowlus 2011). It has also been reported that choledocholithiasis and infections (in the liver, bile ducts, and gallbladder) can cause primary sclerosing cholangitis (Mendes and Lindor 2010). Chronic fatigue, jaundice, itching, malabsorption, cirrhosis, enlarged liver, enlarged spleen, weight and appetite loss, and infection of the bile duct are the most common symptoms of primary sclerosing cholangitis (Miura and Miyachi 2009; Bowlus 2011; Elfaki and Lindor 2011; Ibrahim and Lindor 2011; Singal and others 2011; Azizi and others 2012). There are different medications for the treatment of primary sclerosing cholangitis such as cholestyramine (Mendes and Lindor 2010), ursodeoxycholic acid (Lindor and others 2009), antibiotics (Elfaki and Lindor 2011) (for treatment of bile duct infections), and some immunosuppressive drugs such as prednisone, azathioprine, cyclosporine, and methotrexate (Tabibian and Lindor 2013). Treatments with some vitamins such as vitamin D, vitamin E, vitamin A, and vitamin K have also shown to have some beneficial effects (Ibrahim and Lindor 2011). In addition to drug treatments, surgical procedures may be useful for primary sclerosing cholangitis (Aljiffry and others 2011).
It has been known that curcumin mitigates cholangiopathy and biliary fibrosis in Mdr2−/− mice via targeting the activation of PPARγ in cholangiocytes, inhibiting the TNF-α-induced inflammatory activation and the marker vascular cell adhesion molecule-1 expression in cholangiocytes (Baghdasaryan and others 2010). Through these mechanisms of action, curcumin decreases the attraction of neutrophil granulocytes and myofibroblasts in the portal fields. Furthermore, curcumin inhibits proliferation and portal myofibroblast activation through extracellular signal-regulated kinases1/2 phosphorylation inhibition, and therefore reduced fibrogenesis in Mdr2−/− mice (Baghdasaryan and others 2010).
Conclusion and Recommendation
In conclusion, curcumin shows therapeutic actions in different liver diseases, namely, hepatitis B, hepatitis C, alcoholic liver disease, nonalcoholic fatty liver disease, drug-induced hepatotoxicity, liver cancer, biliary cirrhosis, and primary sclerosing cholangitis. It is a potent free radical scavenger with good hydrogen-donating ability. It is also well known for its good metal chelating effect, especially iron and copper. The molecular mechanisms of curcumin therapeutic actions showed that its antioxidant and inhibitory effects on NF-kB, which is able to regulate different proinflammatory and profibrotic cytokines, have a crucial role in the mitigation of liver diseases. It is well known that oxidative stress has a crucial role in the initiation and progression of several liver diseases. NF-kB is known as one of the most important oxidative damage-responsive transcription factors and is crucial as an inflammatory transcriptional regulator in liver diseases.
Abundance of research shows that NF-kB plays cytoprotective effect and suppresses TNF-α-induced ROS formation through different mechanisms (Bubici and others 2006). NF-kB-mediated overexpression of ferritin heavy chain gene is one of them. Moreover, free iron can easily produce highly reactive hydroxyl radicals through Fenton and Haber–Weiss reactions, so decreasing of free iron level in the cells is necessary and vital (Pham and others 2004). Upregulation of ferritin heavy chain leads to inhibition of TNF-R-induced JNK signaling and cell death (Papa and others 2006). On the other hand, a plethora of information shows that ferritin heavy chain upregulated in tumor cell during their progression in response of oxidative stress (Baldi and others 2005; Aung and others 2007). Hence, NF-kB-promoted ferritin heavy chain over expression may cause tumor progression, anaplasia, and cancer resistance. Upregulation of Mn-SOD is another NF-kB-mediated antioxidant mechanism (Delhalle and others 2002). Pham and others 2004 reported that upregulation of Mn-SOD is dependent of both TNF-α and NF-kB and causes little or even no protection against TNF-R-mediated killing. Although this finding suggests that Mn-SOD probably not involves in the protective role of NF-kB against programmed cell death; there is evidence on correlation between Mn-SOD and pro-oncogenic actions of NF-kB (Bubici and others 2006). Synergism between Mn-SOD and ferritin heavy chain seems essential for suppressing redox homeostasis. Such anticancer agents cause increasing of ROS/JNK signaling in cancerous cells, and hence it is reasonable that blockage of the NF-kB-mediated procedures can commence and reinforce triggering of necrosis signaling in cancerous cell (Pham and others 2007).
Curcumin activates PPAR-γ, inhibits ERK, elevates the cellular GSH content, and inhibits toll-like receptor-4 gene expression leading to downregulation of NF-kB in hepatic stellate cells (Zheng and Chen 2006; Chen and Zheng 2008; Oconnell and Rushworth 2008). These procedures result in the suppression of TGF-β receptor gene expression that leads to inhibiting of TGF-β signaling and suppression of connective tissue growth factor gene expression. The above-mentioned procedures result in the reduction of the production of extracellular matrix from activated hepatic stellate cells and the mitigation of liver injuries (Zheng and Chen 2006). Curcumin ability to inhibit the growth stimulatory pathways such as insulin-like growth factor-1 plays important role in its antiproliferative effects (Xia and others 2007).
In the hepatitis B viral infection, curcumin modifies the PGC-1α level and inhibits the gene expression of HBV. Antioxidant actions of curcumin play a crucial role in its therapeutic actions in hepatitis C viral infection. Also, curcumin suppresses hepatitis C virus replication via PI3K/Akt-SREBP-1 pathway inhibition. In cases of alcoholic liver disease, the protective role of curcumin is due to its mitigating role in alcohol-induced oxidative stress and lipid peroxidation. Curcumin modifies the activation of NF-kB, and also the expression of different cytokines and chemokines. In nonalcoholic fatty liver disease, curcumin ameliorates histopathological abnormality via modification of expression of different cytokines and chemokines. The antioxidant activity of curcumin also plays an important role in its therapeutic action in nonalcoholic fatty liver disease. The antioxidant and anti-inflammatory effects of curcumin appear to have an effective role in the management of drug-induced hepatotoxicity.
There are numerous mechanisms for the beneficial effects of curcumin against liver cancer. In fact, curcumin, as a classical Michael acceptor, and due to the presence of phenolic groups, plays an important role as an anticancer substance. In cases of biliary cirrhosis, antioxidant ability of curcumin and its potential in downregulation of NF-kB and TGF-β play an important role in the mitigation of chronic cholestatic liver inflammation and fibrosis. The preventive role of curcumin against fibrosis may be the result of its antioxidant action. In primary sclerosing cholangitis, curcumin inhibits the attraction of neutrophil granulocytes and myofibroblasts. The following recommendations are important for utilizing curcumin as a validated hepatoprotective agent:
-More basic and clinical studies must be performed on bioavailability, pharmacokinetics, and pharmacodynamic action of curcumin and its derivatives.
-More studies on the improvement of curcumin bioavailability, such as liposomal curcumin, curcumin nanoparticles, curcumin phospholipid complex, and use of curcumin analog must be performed.
-Further studies for ascertaining the best effective dose for the mitigation of liver diseases are needed.