Hepatocellular carcinoma (HCC) is among the most prevalent and deadly cancers worldwide. Prominent risk factors for HCC include viral hepatitis infection; dietary exposure to hepatotoxic contaminants such as aflatoxins; alcoholism; smoking; and male gender. This review highlights ongoing efforts in HCC prevention. Strategies include vaccination against, and treatment of, viral hepatitis infection. In addition to interferon alpha, an acyclic retinoid (all-trans-3,7,11, 15-tetramethyl-2,4,6,10,14-hexadecapentanoic acid), glycyrrhizin and ginseng are currently under clinical investigation for HCC prevention in Japanese hepatitis C patients. Several recent clinical studies in a Chinese region of pervasive aflatoxin contamination also support the approach of favorably altering aflatoxin metabolism and excretion using the chemopreventive agents oltipraz or chlorophyllin. Agents exhibiting chemopreventive efficacy in preclinical HCC models include vitamins A, D, and E, herbal extracts, a 5alpha-reductase inhibitor, green tea, and D-limonene. Efforts to elucidate the molecular lesions and processes underlying HCC development have identified several putative molecular targets for preventive interventions. These include genes and gene products controlling viral replication, carcinogen metabolism, signal transduction, cell-cycle arrest, apoptosis, proliferation, and oxidative stress.
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Accumulation of hydrophobic bile acids during cholestasis leads to generation of oxygen free radicals in the liver. Accordingly, this study investigated whether polyphenols from green tea Camellia sinenesis, which are potent free radical scavengers, decrease hepatic injury caused by experimental cholestasis. Rats were fed a standard chow or a diet containing 0.1% polyphenolic extracts from C. sinenesis starting 3 days before bile duct ligation. After bile duct ligation, serum alanine transaminase increased to 760 U/l after 1 day in rats fed a control diet. Focal necrosis and bile duct proliferation were also observed after 1-2 days, and fibrosis developed 2-3 wk after bile duct ligation. Additionally, procollagen-alpha1(I) mRNA increased 30-fold 3 wk after bile duct ligation, accompanied by increased expression of alpha-smooth muscle actin and transforming growth factor-beta and the accumulation of 4-hydroxynenonal, an end product of lipid peroxidation. Polyphenol feeding blocked or blunted all of these bile duct ligation-dependent changes by 45-73%. Together, the results indicate that cholestasis due to bile duct ligation causes liver injury by mechanisms involving oxidative stress. Polyphenols from C. sinenesis scavenge oxygen radicals and prevent activation of stellate cells, thereby minimizing liver fibrosis.
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BACKGROUND: Recently, considerable attention has been focused on dietary and medicinal phytochemicals that inhibit, reverse, or retard diseases caused by oxidative and inflammatory processes. Green tea polyphenols have both antioxidant and antiinflammatory properties. OBJECTIVE: We examined the effects of green tea polyphenols in carbon tetrachloride-treated mice, a model of liver injury in which oxidant stress and cytokine production are intimately linked. We tested the effect of a pure form of epigallocatechin gallate (EGCG), the major polyphenol in green tea, in mice treated with carbon tetrachloride. DESIGN: Eight-week-old ICR mice were administered 20 microL/CCl(4) kg dissolved in olive oil. Two different doses of EGCG, 50 and 75 mg/kg, were tested. Control mice were treated with saline and olive oil. We analyzed liver histopathology, lipid peroxidation, and messenger RNA and protein concentrations of inducible nitric oxide synthase. Additionally, nitric oxide-generated radicals were assessed by electron paramagnetic resonance spectroscopy, and protein concentrations were measured by immunohistochemistry and Western blot analysis. RESULTS: Carbon tetrachloride administration caused an intense degree of liver necrosis associated with increases in lipid peroxidation, inducible nitric oxide synthase messenger RNA and protein, nitrotyrosine, and nitric oxide radicals. EGCG administration led to a dose-dependent decrease in all of the histologic and biochemical variables of liver injury observed in the carbon tetrachloride-treated mice. CONCLUSIONS: Green tea polyphenols reduce the severity of liver injury in association with lower concentrations of lipid peroxidation and proinflammatory nitric oxide-generated mediators. Green tea polyphenols can be a useful supplement in the treatment of liver disease and should be considered for liver conditions in which proinflammatory and oxidant stress responses are dominant.
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