Dietary tomato powder inhibits alcohol-induced hepatic injury by suppressing cytochrome p450 2E1 induction in rodent models.

Chronic and excessive alcohol consumption leads to the development of alcoholic liver disease (ALD) and greatly increases the risk of liver cancer. Induction of the cytochrome p450 2E1 (CYP2E1) enzyme by chronic and excessive alcohol intake is known to play a role in the pathogenesis of ALD. High intake of tomatoes, rich in the carotenoid lycopene, is associated with a decreased risk of chronic disease. We investigated the effects of whole tomato (tomato powder, TP), partial tomato (tomato extract, TE), and purified lycopene (LYC) against ALD development in rats. Of the three supplements, only TP reduced the severity of alcohol-induced steatosis, hepatic inflammatory foci, and CYP2E1 protein levels. TE had no effect on these outcomes and LYC greatly increased inflammatory foci in alcohol-fed rats. To further support the protective effect of TP against ALD, TP was supplemented in a carcinogen (diethylnitrosamine, DEN)-initiated alcohol-promoted mouse model. In addition to reduced steatosis and inflammatory foci, TP abolished the presence of preneoplastic foci of altered hepatocytes in DEN-injected mice fed alcohol. These reductions were associated with decreased hepatic CYP2E1 protein levels, restored levels of peroxisome proliferator-activated receptor-α and downstream gene expression, decreased inflammatory gene expression, and reduced endoplasmic reticulum stress markers. These data provide strong evidence for TP as an effective whole food prevention strategy against ALD.

Tomato lycopene prevention of alcoholic fatty liver disease and hepatocellular carcinoma development.

Alcoholic liver disease (ALD) is a major cause of morbidity and mortality worldwide. The incidence of hepatocellular carcinoma (HCC) is increasing in the United States, and chronic, excessive alcohol consumption is responsible for 32%-45% of all the liver cancer cases in the United States. Avoidance of chronic or excessive alcohol intake is the best protection against alcohol-related liver injury; however, the social presence and addictive power of alcohol are strong. Induction of the cytochrome P450 2E1 (CYP2E1) enzyme by chronic and excessive alcohol intake is known to play a role in the pathogenesis of ALD. High intake of tomatoes, rich in the carotenoid lycopene, is associated with a decreased risk of chronic disease. The review will overview the prevention of ALD and HCC through dietary tomato rich in lycopene as an effective intervention strategy and the crucial role of CYP2E1 induction as a molecular target. The review also indicates a need for caution among individuals consuming both alcohol and high dose lycopene as a dietary supplement.

Deletion of tumor progression locus 2 attenuates alcohol-induced hepatic inflammation.

BACKGROUND: The pathogenesis of alcoholic liver disease (ALD) involves the interaction of several inflammatory signaling pathways. Tumor progression locus 2 (TPL2), also known as Cancer Osaka Thyroid (COT) and MAP3K8, is a serine-threonine kinase that functions as a critical regulator of inflammatory pathways by up-regulating production of inflammatory cytokines. The present study aims to fill the gap in knowledge regarding the involvement of TPL2 in the mechanism of alcohol-induced hepatic inflammation. METHODS: Male TPL2(-/-) knockout (TPL2KO) mice and TPL2(+/+) wild-type (WT) mice were group pair-fed with Lieber-DeCarli liquid ethanol diet (EtOH diet, 27% energy from EtOH) or control diet (ctrl diet) for 4 weeks. Both histological and molecular biomarkers involved in the induction of hepatic inflammation by alcohol consumption were examined. RESULTS: Consumption of the EtOH diet in WT mice lead to a significant induction of TPL2 mRNA expression as compared with WT mice fed ctrl diet. A significant induction in inflammatory foci and steatosis was also observed in WT mice fed EtOH diet. The deletion of TPL2 significantly reduced inflammatory foci in the liver of mice consuming both ctrl and EtOH diets as compared to their respective WT controls. This reduction was associated with suppression of hepatic inflammatory gene expression of interleukin-6 (IL-6), tumor necrosis factor-α (TNF-α), and interleukin-1ß (IL-1ß) and macrophage marker F4/80. In addition, histological analysis of livers revealed that TPL2 deletion resulted in reduced steatosis in both ctrl (significant) and EtOH (non-significant) diet-fed mice as compared to their respective WT controls. CONCLUSIONS: The demonstration that TPL2 deletion attenuates alcohol-induced hepatic inflammation provides evidence of a novel role for TPL2 in the pathogenesis of ALD.

Carotenoids and alcoholic liver disease.

Chronic and excessive consumption of alcohol leads to the development of alcoholic liver disease. The depletion of vitamin A is a well-known consequence of alcohol consumption, and may be associated with the observed alcohol-induced hepatic injury. The provitamin A carotenoid ß-carotene has been demonstrated to increase alcohol-induced hepatic injury when given in high doses, while low dose supplementation provides protection against hepatic injury. However, it is unknown if the hepatoprotective effects of low dose ß-carotene are due to the protective actions of ß-carotene itself or if the alterations are due to restored vitamin A levels. Future studies are needed to provide further insight into the specific mechanisms by which ß-carotene exerts its protective effect. Further, supplementation studies utilizing high doses of ß-carotene in the presence of alcohol must be done with caution.