Nutrition and Cancer, 60(6), 729–735
Copyright © 2008, Taylor & Francis Group, LLC
ISSN: 0163-5581 print / 1532-7914 online
DOI: 10.1080/01635580802419772
Potential Role of Lycopene in the Treatment of Hepatitis C
and Prevention of Hepatocellular Carcinoma
Soley Seren
Department of Medicine, Wayne State University, Detroit, Michigan, USA
Milton Mutchnick and Daryl Hutchinson
Department of Medicine and Division of Gastroenterology, Wayne State University, Detroit,
Michigan, USA
Ozgur Harmanci and Yusuf Bayraktar
Department of Medicine, Division of Gastroenterology, Hacettepe University, Ankara, Turkey
Sean Mutchnick
Department of Medicine and Division of Gastroenterology, Wayne State University, Detroit,
Michigan, USA
Kazim Sahin
Department of Animal Nutrition, Faculty of Veterinary Science, Firat University, Elazig, Turkey
Omer Kucuk
Department of Medicine and Division of Hematology and Oncology, Wayne State University, Detroit,
Michigan, and Barbara Ann Karmanos Cancer Institute, Detroit, Michigan, USA
Hepatitis C virus (HCV) infection and hepatocellular carcinoma
(HCC) are growing health problems around the world. Oxidative
stress plays a significant role in the initiation and progression of
hepatocellular damage and possibly in the development of HCC in
HCV infected patients. In vitro, animal and clinical studies suggest that lycopene, a nonprovitamin A carotenoid and a potent
antioxidant, may attenuate the liver injury and possibly prevent
the development of HCC. In this article, we discuss the relationship between HCV infection and oxidative stress and review the
potential role of lycopene in the treatment of HCV and prevention
of HCC.
INTRODUCTION
Hepatitis C virus (HCV) infection is a global public health
problem. It is estimated that approximately 3.1% of the world
population are chronically infected with HCV. In the United
States, at least 2.7 million people are believed to be chronically
Submitted 29 August 2007; accepted in final form 14 July 2008.
Address correspondence to Omer Kucuk, Emory Winship Cancer
Institute, 1365-C Clifton Road NE, Atlanta, GA 30322. Phone: 404778-5903. Fax: 404-778-5676. E-mail: [email protected]
HCV infected. End stage liver disease due to chronic HCV infection is the most common indication for liver transplantation, and
HCV is one of the most common causes of hepatitis, cirrhosis,
and hepatocellular carcinoma (HCC) in the United States (1).
In contrast to acute hepatitis B infection in which spontaneous resolution of infection can occur in a proportion of patients throughout the course of the disease, it appears that spontaneous resolution of well-established chronic hepatitis C (CHC)
is unusual after the first year or two of HCV infection. Overall,
about 75–85% of acute HCV infections become chronic infections. It has been estimated that approximately 30% of patients
with chronic HCV infection are at risk for developing long-term
complications such as cirrhosis and HCC (2).
It has been estimated that within the next 10 yr, over 800,000
Americans will develop advanced HCV-related liver disease due
to progression of disease, and the number of liver disease related
deaths in the United States is likely to exceed 40,000/year by
2040 (3). Thus, there is an urgent need for continued optimization of anti-HCV therapies to reduce HCV-associated mortality
and morbidity in the coming decades.
In this article, we review the association of oxidative stress
with HCV infection, and we discuss the potential role of lycopene in the treatment of CHC and in the prevention of its
progression to cirrhosis and HCC.
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S. SEREN ET AL.
FIG. 1. Lycopene structure: Lycopene is a terpene, assembled from 8 isoprene units.
Lycopene
Lycopene is an open-chain, unsaturated carotenoid with a
molecular formula C40 H56 (Fig. 1). It is responsible for the
red color in fruits and vegetables like tomatoes, watermelon,
grapefruit, guava, rosehip, and red chilies. Its name is derived
from the tomato’s species classification Solanum lycopersicum.
Almost all dietary lycopene comes from tomato and tomato
product consumption (4). Following absorption into enterocytes, all carotenoids including lycopene are incorporated into
triglyceride-rich chylomicron particles for transport to the liver,
the major storage site. In the body, lycopene is also deposited
in the lungs, prostate gland, testes, colon, and skin. Secondary
organs are supplied lycopene from the liver lycopene pool (5).
Its concentration in body tissue tends to be higher than all other
carotenoids.
Lycopene, a nonprovitamin A carotenoid, is the most efficient
singlet-oxygen (a reactive oxygen species) quencher among the
natural carotenoids. In healthy human subjects, lycopene- or
tomato-free diets result in loss of lycopene and an increase in
lipid oxidation. The plasma depletion half-life of lycopene was
estimated to be between 12 to 33 days. Moxley et al. (6) showed
that healthy individuals consuming a lycopene free diet exhibit
a decrease in total serum lycopene of 49% in 14 days. One
study has shown that lycopene may have cholesterol lowering
properties similar to statins (7).
Although best known as an antioxidant, both oxidative and
nonoxidative mechanisms may be involved in lycopene’s biological activity. The biological activities of certain carotenoids
such as β-carotene are related to their ability to form vitamin A within the body. Because lycopene lacks a β-ionone
ring structure, it cannot form vitamin A, and its biological effects in humans has been attributed to mechanisms other than
vitamin A. Lycopene’s configuration enables it to inactivate
free radicals and to interfere with free-radical-initiated reactions, particularly lipid peroxidation, thereby preventing tissue
injury (8). Because free radicals are electrochemically imbalanced molecules, they are highly reactive and capable of reacting with cell components and causing permanent damage.
These toxic chemicals are formed naturally as by-products during oxidative cellular metabolism, infections, and inflammation.
Lycopene has singlet-oxygen-quenching ability twice that of βcarotene and 10 times higher than that of α-tocopherol (vitamin E). Its oxygen-quenching ability protects against oxidative
DNA damage in vitro and in vivo, thereby preventing potential
mutations that may be associated with cancer initiation and progression (9,10). In an organic solution, lycopene was the most
rapidly destroyed carotenoid on reaction with peroxyl radicals,
indicating its presence in the first line of defense (11). However,
studies have shown that the antioxidant effects of lycopene are
not powerful enough by themselves to protect liver tissue in the
event of acute injury due to oxidative stress (12).
Oxidative Stress and Hepatitis C Viral Infection
The involvement of oxidative stress in the pathogenesis of
hepatitis and HCC has been strongly suggested (13). Increased
oxidative DNA damage was found not only in hepatitis C but
also in transgenic mice expressing hepatitis B virus (14). However, the role of oxidative stress in the progression of chronic
hepatitis and hepatocarcinogenesis may be greater in hepatitis C
than in other types of hepatitis such as hepatitis B or autoimmune
hepatitis (15). Oxidative stress refers to an imbalance between
the oxidation reaction caused by reactive oxygen species (ROS)
and the antioxidation reaction caused by antioxidant molecules
such as lycopene.
The main source of ROS in hepatocytes is the mitochondria. Hepatocytes contain many mitochondria and thus have
high production of ROS. In HCV core gene transgenic mice,
the malfunction of the electron transfer system of mitochondria has been suggested as an origin of ROS overproduction
(13). Additionally, on viral infection, there is a greater degree
of ROS production in inflammatory cells by nicotinamide adenine dinucleotide phosphate (NADPH) oxidase and xanthine
oxidase (31)which is induced by HCV proteins, especially NS3
(a nonstructural protein) (14). Normally, superoxide radical produced in mitochondria is converted to water by detoxification
enzymes such as superoxide dismutase and glutathione peroxidase (GPX). However, when these enzymes can not convert
the superoxide radicals to water fast enough, oxidative damage
occurs in mitochondria. In Hepatitis C, increased production
of ROS and the accumulation of mitochondrial DNA damage
resulting in mitochondrial dysfunction has been shown (15).
Also, HCV RNA was reported to induce nitric oxide synthase
(iNOS), which results in increased nitric oxide, a strong oxidant.
Indeed, iNOS synthesis was found to be correlated with the intrahepatic viral load in CHC (16). Moreover, cytokines released
from inflammatory cells may further induce ROS production
from hepatocytes.Another important mechanism of oxidative
stress was postulated to be the excessively high iron content
in the liver of CHC patients (17). Free iron has been shown
to catalyze reactions producing highly reactive HO· (hydroxyl
radical), leading to more cellular membrane oxidation and lipid
peroxidation (18). The fact that iron removal therapy significantly improves the serum ALT levels in CHC patients supports
the close relationship between oxidative stress and liver damage
in CHC (19).
LYCOPENE, HCV, AND HCC
Antioxidant Depletion in Chronic Hepatitis C
In previous clinical studies, it has been shown that antioxidants (AO) are severely depleted in serum and liver tissue of
patients with chronic hepatitis C infection (20). The inverse
relationship between serum antioxidants and viral disease progression has been demonstrated in several studies. In 1 of these,
Yadav et al. (21) analyzed serum and liver levels of retinol,
tocopherols, lutein, lycopene, α-carotene and β-carotene, and
the lipid peroxidation product malondialdehyde (MDA) in 20
patients with CHC and compared them to the 22 healthy individuals who were not on any vitamin supplements. Patients with
CHC had lower serum and liver AO levels and higher serum
MDA levels. Both MDA and AO levels were correlated with
the degree of fibrosis and inflammation in the liver. This study
suggests that increasing fibrosis associated with decreased liver
antioxidant levels may be a consequence of AO depletion due to
oxidative stress or decreased AO storage due to fibrosis. Antioxidant depletion in the liver is postulated to play a role even at the
early stages of liver injury until subsequent cirrhosis and HCC
develops. Yamamoto et al. (22) measured the oxidized form
of ubiquinol-10 (lipid-soluble antioxidant, ubiquinone-10) in
plasma of patients with chronic active hepatitis, cirrhosis, and
HCC. All groups had a significant increase in ubiquinone-10
percentage, with highest levels observed in patients with HCC.
Additionally, there may be a functional defect in the mobilization of AO from the liver in patients with CHC. Rocchi et al.
(23) showed decreased serum levels of AO in patients with
CHC.
Oxidative Stress and Hepatic Fibrosis
Oxidative stress leads to hepatic fibrosis, which is now believed to be the most important prognostic factor determining
the progression of liver disease in CHC (24). Currently, one of
the more common causes of hepatic fibrosis is CHC infection
in which hepatic steatosis is frequently observed. It has been
suggested that HCV nonstructural core protein plays a crucial
role in hepatic steatosis (25). Hepatic steatosis leads to an increase in lipid peroxidation and oxidative stress in hepatocytes,
which stimulates further lipid peroxidation and hepatic steatosis
leading to necroinflammation. The lipid peroxides formed can
be chemotactic for neutrophils, causing increased inflammation,
which further drives oxidant-mediated injury in the liver (26).
Enhanced oxidative stress also initiates a fibrogenesis cascade in
the liver of patients with CHC infection and mediates activation
of collagen type I gene expression from hepatic stellate cells
(HSC) (27,28). HSCs are regarded as the primary target cells
for inflammatory stimuli and produce extracellular components
like collagen, which leads to fibrosis.
Antioxidants in the Treatment of Chronic Hepatitis C
Previous clinical trials have suggested that antioxidant therapy may have a beneficial effect in patients with CHC infection.
Although clinical studies with AO have been conducted in pa-
731
tients with CHC, lycopene has not been studied alone or in
combination with antiviral treatment in CHC. Melhem et al.
(29) conducted a Phase I clinical trial assessing 50 CHC patients treated with 7 antioxidative oral preparations along with 4
different intravenous preparations daily for 10 wk, monitoring
HCV-RNA levels, liver enzymes, and liver histology. The results showed normalization of liver enzymes in 44% of patients,
a decrease in viral load in 25% of the patients, and histologic
improvement (2-point reduction in the hepatic activity index,
HAI score) in 36.1% of the patients. Treatment was well tolerated by all, and no side effects were noted. In another study,
23 CHC patients refractory to α-interferon therapy were treated
with high dose vitamin E (α-tocopherol), a lipid-soluble antioxidant, for 12 wk. In 11 of 23 patients, aminotransferases
ALT and AST were lowered by 46% and 35%, respectively,
but was followed by a rapid relapse on cessation of treatment
with vitamin E (30). Similarly Mahmood et al. (31) had demonstrated decreased serum ALT and thioredoxin (TRX, antioxidant) following the administration of vitamin E. It supports the
idea that viral hepatitis is associated with inflammatory events
known to be directly related to formation of reactive oxygen
species capable of inducing oxidative damage to cellular membranes and DNA. There have been mixed results of N-acetyl
cysteine administration in patients with CHC. Ideo et al. (32)
conducted a randomized clinical trial assessing the efficacy of αinterferon (IFN) in combination with the antioxidants N-acetyl
cysteine and vitamin E in patients who had no response to previous course of IFN therapy. Neither end of treatment response
(ETR) nor sustained viral response (SVR) was improved by
combination therapy. In contrast, Beloqui et al. (33) reported
decreased transaminases and viral load with combined N-acetyl
cysteine and IFN therapy in IFN-unresponsive patients. Interferon administration alone was demonstrated to decrease levels
of hydroxyl-2-nonenal (HNE, a peroxidation reaction product
of lipids) markedly in patients with CHC (34). This benefit of
current antiviral therapy could be enhanced by the coadministration of antioxidants like lycopene.
As stated above, steatosis or steatohepatitis (SH) is the initial step in the fibrosis cascade, and its significance on response
to treatment of CHC has been shown by Harrison et al. (35).
The overall SVR in patients with CHC plus steatosis or SH
was 28% compared with 44% in patients with CHC without
any steatosis or SH. Another significant observation in patients
with CHC who respond to antiviral treatment was an increased
caspase activity and production of apoptosis-associated proteins
(P < 0.05) when compared to nonresponders. This was closely
correlated with virus elimination. Lycopene has been shown to
activate the caspase system. In addition to lycopene’s antioxidant effects, enhanced caspase activity might play a role in
HCV clearance and could also predict the efficacy of antiviral
treatment (36).
Although eradication of HCV RNA is the primary goal of
treatment, oxidative stress and lipid peroxidation play major
roles in the fatty accumulation in the liver and development of
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S. SEREN ET AL.
hepatic fibrosis in CHC. These are the most important prognostic factors determining the progression of liver disease. Antioxidants may have a secondary benefit of reducing progression
to fibrosis, thereby decreasing the progression to cirrhosis or
possibly reversing early cirrhosis. In the long term, there may
be a lower frequency of development of HCC (37). Further
clinical trials should be conducted to assess the effect of antioxidants in the treatment of CHC and on disease progression.
Lycopene, a powerful antioxidant compound, could break this
oxidative stress-fibrosis cycle and also decrease hepatic necroinflammation by its anti-inflammatory effects.
Hepatocarcinogenesis and Oxidative Stress
Oxidative stress has been postulated to play an important role
in hepatocarcinogenesis in CHC (38). As mentioned previously,
mitochondrial DNA, the major source of ROS production in
the liver, lacks the protective mechanisms, so it is more susceptible to ROS induced mutations. It is believed that viral core
protein acts on the function of mitochondria, leading to overproduction of oxidative stress, which yields genetic aberrations
in cell-growth-related genes (38). Both malignant and nonneoplastic liver tissues in patients with HCC showed very high
indexes of mitochondrial DNA mutations, which can explain
the relationship between oxidative stress induced DNA damage
and HCC development (39). Both mitochondrial oxidative stress
and endoplasmic reticulum (ER) stress has been hypothesized to
result in intracellular and extracellular accumulation of DNAdamaging factors that could predispose a cell to mutagenesis
(40).
Lycopene and HCC
The unusually high concentration of lycopene in the liver
has prompted researchers to explore the association of lycopene
and risk of HCC (Table 1). Evolving evidence suggests that
carotenoids may modulate processes related to mutagenesis,
carcinogenesis, cell differentiation, and proliferation independent of their roles as AOs or precursors of vitamin A (46,47).
Potential Mechanisms of Lycopene in Cancer Prevention
The postulated anticarcinogenic mechanisms of action of
lycopene include a) inhibition of proliferation and induction
of differentiation in cancer cells by modulating the expression
of cell cycle regulatory proteins (48), b) modulation of the IGF1/IGFBP-3 system (49), c) upregulation of gap-junctional gene
connexin 43 (Cx43) and increased gap junctional intercellular
TABLE 1
Lycopene and hepatocellular cancera
Reference Author
Study Type
59
In vitro
60
61
62
Hepatocellular Carcinoma
Hepatocellular carcinoma has become a disease of increased
significance in the United States. Surveillance, Epidemiology,
and End Results (SEER) data showed a doubling of HCC incidence rates in the United States between 1985 and 1998, reaching 4.1 per 100,000 persons in 2000, with a greater increase in
the incidence rates in younger age groups (41,42).
Worldwide, liver cancer is the third most common cause
of cancer mortality, with approximately 550,000 annual deaths
(43). Liver cancer is the 8th most frequent cause of cancer
mortality in U.S. men and the 12th in women (44). The American
Cancer Society estimated 14,270 deaths from liver cancer in the
United States in 2004, of which 70%–80% were HCC.
Chronic infection with HCV and/or hepatitis B virus (HBV)
is associated with the majority of HCC cases. Recent estimates
for the United States have attributed 47% of cases to HCV
alone, 15% to HBV alone, and 5% to coinfection with both
viruses (45). The remaining 33% of cases appear to be due to
nonviral causes. Once HCV infection develops into cirrhosis,
HCC develops at an annual rate of 5–7% (42).
63
67
68
65
66
Park
Effects of Lycopene
Decreased growth of
Hep3B hepatoma
cells
Hwang
In vitro
Decreased invasiveness
of SK-Hep1
hepatoma cells
Reddy
In vitro
Protection of
hepatocytes from
aflatoxin
carcinogenicity
Yu
Epidemiology Decreased risk of
alcohol induced HCC
Watanabe Rat
No effect on
development of HCC
in LEC rats
Astorg
Rat
Inhibition of initiation
of liver preneoplastic
foci
Gradlet
Rat
Inhibition of
aflatoxin-induced
liver preneoplastic
foci
Yu
Clinical
Decreased
aflatoxin-DNA
adducts in urine of
men
Nishino Clinical
Decreased HCC
chronic
hepatitis/cirrhosis
patients
a
Abbreviations are as follows: Hep3B, hepatitis 3B; HCC, hepatocellular carcinoma; LEC, Long-Evans Cinnamon.
LYCOPENE, HCV, AND HCC
communication (50), d) modulation of redox signaling (51),
e) prevention of oxidative DNA damage (52,53), f) inhibition
of IL-6 and androgen (54), g) inhibition of 5-lipoxygenase (55),
h) modulation of carcinogen metabolizing enzymes (56) and
i) modulation of immune function (57). Brienholt et al. (58) also
found that lycopene significantly induces phase I enzymes, such
as cytochrome P450-dependent enzymes, in a dose-dependent
manner and hepatic quinone reductase (QR), a phase II enzyme,
by twofold. This class of enzymes is important for the removal
of the foreign substances and carcinogens from the body.
Lycopene is thought to inhibit proliferation of cancerous cells
at the G0-G1 cell cycle phase. In a study on Hep3B human
hepatoma cell line, lycopene induced G0/G1 arrest, S phase
block, and cell growth inhibition in a dose-dependent manner
by almost 40% (59). In addition, lycopene’s antimetastatic
properties were shown by adhesion and migration assays on
SK-Hep1 human hepatoma cell line. Invasiveness of the cells
was reduced by 62% after treatment with 10 mM lycopene (60).
Lycopene has been reported to inhibit the hepatotoxic and
carcinogenic effects of aflatoxin B1, alcohol, and smoking.
Reddy et al. (61) observed that hepatocytes pretreated with lycopene and β-carotene were protected from the effects of the
hepatocarcinogen aflatoxin at both cellular and molecular levels.
Yu et al. (62) reported that the effect of alcohol consumption and
tobacco smoke on HCC was significantly higher among patients
with low plasma levels of carotenes and lycopene compared to
those with high levels. However, in a study with Long-Evans
Cinnamon rats, lycopene administration did not reduce the risk
of spontaneous liver carcinogenesis (63).
To date, there have been few randomized clinical trials testing the chemopreventive effect of antioxidants on hepatocarcinogenesis. In 1 clinical trial, Takagi et al. (64) divided 83
patients with liver cirrhosis and chronic HCV infection into
two groups. After a follow-up of 5 yr, cumulative tumor-free
survival and cumulative overall survival rates were higher in
the vitamin E group compared to the control group, but this
was not statistically significant. Neither improvement in liver
function, cumulative survival, or suppression of hepatocarcinogenesis could be demonstrated in the vitamin E group.
Only 1 case-control study has examined the relationship between lycopene and aflatoxin B1 (AFB1 ) initiated hepatocellular carcinoma. Lycopene was thought to influence the binding of AFB1 to hepatic DNA. The urine level of the major
in vivo AFB1 -DNA adduct, AFB1 -N7 -guanine, was significantly higher in subjects with HCC than in controls (HCC
odds ratio = 7.52) and was inversely related to the plasma
lycopene level (65). A recent randomized clinical trial in patients with chronic hepatitis and cirrhosis showed that the subjects who took a carotenoid mixture containing lycopene developed significantly less HCC compared to the control subjects
(66).
In an animal model of hepatocarcinogenesis in rats, lycopene
decreased the size of preneoplastic foci in liver induced by
diethylnitrosamine but did not reduce the number of lesions (67).
733
In a separate mouse study, lycopene (0.005% in drinking water)
was given to 30 C3H/He male mice for 40 wk. In contrast Gradlet
et al. (68) demonstrated that lycopene reduced the number of
liver tumor-bearing mice by 49.7% (88.2% for control vs. 38.5%
for lycopene-treated mice) and reduced the average number of
tumors per mouse by 88% (7.65–0.92).
Because studies have suggested that lycopene has both antiviral and anticarcinogenic effects on virulent strains of some
viruses, the potential prevention of liver HCC by administering
lycopene along with antiviral treatment in HCV is an attractive concept. Previous studies have shown that increased lycopene levels have been associated with increased clearance of
oncogenic human papilloma virus (HPV) infection (69). Lycopene and other AOs have shown similar anticarcinogenic
effects. Beck et al. (70) demonstrated that selenium deficient
mice are more prone to develop mutations in the viral genome
of both the coxsackie and influenza viruses. Selenium deficiency in mice was associated with conversion of nonvirulent
strains of virus to virulent strains suggesting that not only lycopene but other antioxidant micronutrients may have a role in
mutagenesis.
CONCLUSION
There appears to be an impairment of the antioxidant system
in CHC, and oxidative stress plays a central role in the pathogenesis and progression of the disease. Lycopene is a powerful
antioxidant and may counteract the liver damage in CHC. Accumulating evidence from cell culture, epidemiologic, animal,
and human clinical trials suggests a potential role for lycopene
in the prevention of HCC. In addition, lycopene may also enhance overall response rate to antiviral therapy and delay the
progression of disease. Further clinical trials are needed to further investigate the potential role of lycopene in decreasing the
risk of hepatocellular cancer as well as its potential use as an
adjunct to antiviral therapy.
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