Background
The transcription factor NF-kB is involved in a number of tissues that are sensitive to alcohol. NF-kB is expressed in fetal and brain cells and is known to be sensitive to oxidative stress that could involve activation of NF-kB in alcohol induced fetal toxicity, brain damage, and liver disease. In the latter disorder, chronic alcohol use results in increased levels of endotoxin in the portal circulation, thereby activating Kupffer cells to produce toxic mediators that cause alcoholic liver disease (ALD).
Previous research has tested the hypothesis that inhibiting the activation of NF-KB would protect against experimental ALD. Inhibition of NF-KB by delivery of an adenoviral vector encoding the transgene for an IKB super-repressor prevented alcohol-induced liver injury. With that finding, the scientific community deemed it important to determine whether pharmacological approaches can be developed to suppress the activation of NF-KB and thereby prevent ALD.
Curcumin, the substance that gives turmeric its yellow color, and found in curry, has been found to consist of a natural anti-inflammatory compound. Scientists have already shown that it can suppress tumor blood vessel growth and the activation of NF-KB. This raises the possibility that the substance might be useful in preventing ALD.
Accordingly, an international research team set out to establish whether treatment with curcumin could suppress the expression of NF-KB-dependent genes and prevent ALD. In a rat study they found that curcumin prevented ALD, at least in part, by inhibiting lipid peroxidation, activation of NF-KB, and expression of pro-inflammatory mediators. As in previous findings, the Kupffer cell appeared to be centrally involved in this process.
The authors of "Curcumin Prevents Alcohol-Induced Liver Disease in Rats by Inhibiting the Expression of NF-KB-Dependent Genes," are Amin A. Nanji, from the University of Pennsylvania Medical Center, Philadelphia, PA; Kalle Jokelainen, at the Helsinki University Central Hospital, Helsinki, Finland; George L. Tipoe, from the University of Hong Kong, Hong Kong; Amir Rahemtulla, from the Harvard Medical School, Boston, MA; Peter Thomas, from the Boston University School of Medicine in Boston; and Andrew J. Dannenberg from the Weill Medical College of Cornell University and Anne Fisher Nutrition Center at the Strang Cancer Prevention Center, New York, NY. Their findings appear in the February 2003 edition of the American Journal of Physiology – Gastrointestinal and Liver Physiology. The journal is one of 14 published monthly by the American Physiological Society (APS).
Methodology
Four groups of rats (six in each group) were treated by intragastric infusion (direct placement into the gastric system) for four weeks. One group received fish oil plus ethanol (FE); a second group received fish oil plus dextrose (FD). The third and fourth groups received FE or FD supplemented with curcumin. The test animals were dissected with their liver samples were analyzed for histopathology, lipid peroxidation, NF-KB binding, TNF-á, IL-12, monocyte chemotactic protein-1, macrophage inflammatory protein-2, cyclooxygenase-2 (COX-2), inducible nitric oxide synthase (iNOS), and nitrotyrosine.
Results
In each of the four groups, the rats increased their weight at a constant rate. Moreover, there was no difference in weight gain among the groups. There was also no difference in levels of blood alcohol in the two alcohol-fed groups.
Major findings included:
-
(1) Curcumin inhibits alcohol-induced liver injury and lipid peroxidation. Feeding rats the FE diet for four weeks caused fatty liver, necrosis, and inflammation.
Treatment with curcumin prevented both alcohol-induced necrosis and inflammation. The degree of fatty liver also decreased in curcumin-treated rats. Neither histological nor biochemical evidence of liver injury was detected in rats that received FD or FD-curcumin diets.
(2) Effect of curcumin on activation of NF-KB in liver: The FE diet led to increased NF-KB binding activity compared with the FD diet. Interestingly, curcumin prevented the activation of NF-KB in rats fed the FE diet consistent with its ability to inhibit lipid peroxidation and liver injury. To determine whether activation of NF-KB was a consequence of degradation of IKBá we determined levels of IKBá in the cytosolic fraction of the liver. Very low levels of IKBá were detected in the FE group. By contrast, higher levels of IKBá were detected in the other groups including the FE-curcumin group.
(3) Effect of curcumin on TNF-á, IL-12, MCP-1, MIP-2, COX-2, and iNOS mRNAs in liver. Various NF-KB responsive genes including TNF-á, IL-12, MCP-1, MIP-2, COX-2 and iNOS have been found to be overexpressed in experimental ALD.
The researchers found markedly elevated levels of these proinflammatory mediators in the livers of rats fed FE vs. FD diet. Remarkably, treatment with curcumin resulted in a normalization of levels of each of the these proinflammatory mediators.
Conclusions
Dr. Nanji and his team found that that alcohol-induced liver injury was associated with increased amounts of lipid peroxidation and the induction of multiple NF-KB -dependent genes including TNF-á, IL-12, MCP-1, MIP-2, COX-2, and iNOS. Each of these genes has been implicated in the causation of liver injury, and other liver disease showing inflammatory changes (such as Hepatitis C).
Not only did curcumin prevent alcohol-induced necroinflammatory changes, the yellow pigment from roots and pods of Curcuma longa stopped lipid peroxidation and the expression of the NF-KB-dependent genes. Although curcumin is known to inhibit the activation of NF-KB and suppress inflammation, this is the first time it has been shown to prevent ALD. Whether curcumin can also be used to treat established ALD is uncertain and requires further investigation. Because curcumin can be given safely to humans - taken orally, as in milk or food -- the results of this study have potentially important therapeutic implications for individuals at risk for ALD.
Next Steps for Research
Dr. Nanji's research is now focusing on whether such a compound will be useful in diseases such as non-alcoholic steatohepatitis. Steatohepatitis can lead to liver cirrhosis and liver cancer. Dr. Nanji is investigating whether curcumin can be useful in combating this disease.
Source: February 2003 edition of the American Journal of Physiology--Gastrointestinal and Liver Physiology.
The American Physiological Society (APS) was founded in 1887 to foster basic and applied science, much of it relating to human health. The Bethesda, MD-based Society has more than 10,000 members and publishes 3,800 articles in its 14 peer-reviewed journals every year.
Contact: Donna Krupa:
703-527-7357
Cell: 703-967-2751 or
djkrupa1@aol.com