Genetic polymorphisms of aldehyde dehydrogenase 2, cytochrome p450 2E1 for liver cancer risk in HCV antibody-positive japanese patients and the variations of CYP2E1 mRNA expression levels in the liver due to its polymorphism.
ABSTRACT Hepatocellular carcinoma (HCC) in persons with liver cirrhosis (LC) arises following hepatitis virus infection. Alcohol may accelerate the risk of development of LC and HCC. Cytochrome p450 2E1 (CYP2E1) oxidizes ethanol to form acetaldehyde and aldehyde dehydrogenase 2 (ALDH2) detoxifies acetaldehyde, which is carcinogenic in humans, and both alcohol-metabolizing enzymes show the genetic polymorphisms in a Japanese population.
Using polymorphism analysis, we studied the frequency of ALDH2 functional deletion due to the G to A single-bp mutation in exon 12 and CYP2E1 polymorphism in the transcriptional region, both associated with higher levels of acetaldehyde, in 135 patients with LC and/or HCC, including 99 with HCC, and 135 non-cancer controls. The mRNA expression levels of CYP2E1 in the liver were also examined in 55 surgical specimens.
The allelic frequency of the homozygous ALDH2 2-2 genotype, coding for the enzyme deletion, was significantly higher compared to that of the homozygous or heterozygous ALDH2 1-1 genotypes in cases with HCC (OR = 5.4, 95% CI 2.1-14.0). There were no differences in the frequencies of specific genotypes of CYP2E1 in cases of HCC, but combined analysis of ALDH2 and CYP2E1 revealed that the odds ratio of occurrence of the C1/C1 homozygosity of CYP2E1 and the ALDH2 2-2 homozygosity was as high as 23.0 (2.9-182). The mRNA levels of CYP2E1 were higher in the liver of patients with the C1/C1 homozygosity of CYP2E1 than in those with other genotypes (P < 0.05).
ALDH2 and CYP2E1 polymorphisms may modify the risk of development of HCC against the background of LC in the Japanese. Polymorphism analysis of alcohol-metabolizing enzymes using molecular techniques may be useful in the risk assessment of liver cancer in patients with hepatitis C virus infection.
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ABSTRACT: Alcohol drinking increases the risk for a number of cancers. Currently, the highest risk (Group 1) concerns oral cavity, pharynx, larynx, esophagus, liver, colorectum, and female breast, as assessed by the International Agency for Research on Cancer (IARC). Alcohol and other beverage constituents, their metabolic effects, and alcohol-related unhealthy lifestyles have been suggested as etiological factors. The aim of the present survey is to evaluate the carcinogenic role of acetaldehyde in alcohol-related cancers, with special emphasis on the genetic-epidemiological evidence. Acetaldehyde, as a constituent of alcoholic beverages, and microbial and endogenous alcohol oxidation well explain why alcohol-related cancers primarily occur in the digestive tracts and other tissues with active alcohol and acetaldehyde metabolism. Genetic-epidemiological research has brought compelling evidence for the causality of acetaldehyde in alcohol-related cancers. Thus, IARC recently categorized alcohol-drinking-related acetaldehyde to Group 1 for head and neck and esophageal cancers. This is probably just the tip of the iceberg, since more recent epidemiological studies have also shown significant positive associations between the aldehyde dehydrogenase ALDH2 (rs671)*2 allele (encoding inactive enzyme causing high acetaldehyde elevations) and gastric, colorectal, lung, and hepatocellular cancers. However, a number of the current studies lack the appropriate matching or stratification of alcohol drinking in the case-control comparisons, which has led to erroneous interpretations of the data. Future studies should consider these aspects more thoroughly. The polymorphism phenotypes (flushing and nausea) may provide valuable tools for future successful health education in the prevention of alcohol-drinking-related cancers.Advances in Experimental Medicine and Biology 01/2015; 815:41-58. DOI:10.1007/978-3-319-09614-8_3 · 2.01 Impact Factor
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ABSTRACT: Emerging evidence suggests that a common functional polymorphism, rs4444903 (A>G), in the EGF gene might impact an individual's susceptibility to liver cancer; however, individually published results are inconclusive. This meta-analysis aimed to derive a more precise estimation of the relationship between the EGF rs4444903 polymorphism and liver cancer risk. A literature search was conducted in the PubMed, Embase, Web of Science, and CBM databases from inception through May 1st, 2013. Seven case-control studies were included with a total of 1408 liver cancer cases and 1343 healthy controls. Crude odds ratios (ORs) with 95% confidence intervals (CIs) were calculated. Our meta-analysis results indicated that the G variant of the rs4444903 polymorphism might be associated with an increased risk of liver cancer (G allele vs A allele: OR = 1.25, 95%CI = 1.01-1.56, P = 0.040; GG + AG vs AA: OR = 1.65, 95%CI = 1.27-2.15, P < 0.001; GG vs AA: OR = 1.77, 95%CI = 1.34-2.35, P < 0.001). Further subgroup analysis by ethnicity also showed significant associations between the G variant of the rs4444903 polymorphism and an increased risk of liver cancer among Asian, Caucasian, and African populations. No publication bias was detected in this meta-analysis. In conclusion, the current meta-analysis suggests that the G variant of the rs4444903 polymorphism may increase the risk of liver cancer. The EGF rs4444903 (A>G) polymorphism can be useful as a biomarker in predicting the development of liver cancer.Genetics and molecular research: GMR 01/2014; 13(4):8066-8079. DOI:10.4238/2014.October.7.1 · 0.85 Impact Factor
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ABSTRACT: It is known that chronic ethanol significantly impairs liver regeneration. However, the effect of acute ethanol exposure on liver regeneration remains largely unknown. To address this question, C57Bl6/J mice were exposed to acute ethanol (6 g/kg i.g.) for 3 days and partial hepatectomy (PHx) was performed 24 h after the last dose. Surprisingly, acute ethanol preexposure promoted liver regeneration. This effect of ethanol did not correlate with changes in expression of cell cycle regulatory genes (e.g., cyclin D1, p21 and p27), but did correlate with protection against the effect of PHx on indices of impaired lipid and carbohydrate metabolism. Ethanol preexposure protected against inhibition of the oxidant-sensitive mitochondrial enzyme, aconitase. The activity of aldehyde dehydrogenase 2 (ALDH2) was significantly increased by ethanol preexposure. The effect of ethanol was blocked by inhibiting (daidzin) and was mimicked by activating (alda-1) ALDH2. Lipid peroxides are also substrates for ALDH2; indeed, alcohol preexposure blunted the increase in lipid peroxidation (4OH-nonenal adducts) caused by PHx. Taken together, these data suggest that acute preoperative ethanol exposure 'preconditions' the liver to respond more rapidly to regenerate after PHx by activating mitochondrial ALDH2, which prevents oxidative stress in this compartment.AJP Gastrointestinal and Liver Physiology 10/2013; 306(1). DOI:10.1152/ajpgi.00085.2013 · 3.74 Impact Factor