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.
- SourceAvailable from: Marija StankovicJournal of Medical Biochemistry 01/2015; 34(2). DOI:10.2478/jomb-2014-0024 · 1.08 Impact Factor
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ABSTRACT: Published data on any association between the CYP2E1 RsaI/PstI (c1/c2) polymorphism and liver cancer risk among east Asians are inconclusive. The aim of this Human Genome Epidemiology (HuGE) review and meta- analysis was to derive a more precise estimation of the relationship. A literature search of Pubmed, Embase, Web of science and CBM databases from inception through July 2012 was conducted. Twelve case-control studies were included with a total of 1,552 liver cancer cases and 1,763 healthy controls. Crude odds ratios (ORs) with 95% confidence intervals (CIs) were used to assess the strength of association under five genetic models. When all the eligible studies were pooled into the meta-analysis, the results showed that the c2 allele and the c2 carrier (c2/c2 + c2/c1) of RsaI/PstI polymorphism were associated with decreased risk of liver cancer among east Asians (c2 vs. c1: OR = 0.75, 95%CI: 0.59-0.95, P = 0.016; c2/c2 + c2/c1 vs. c1/c1: OR = 0.76, 95%CI: 0.58-1.00, P = 0.050). In the stratified analysis by country, significant associations were observed between RsaI/PstI polymorphism and decreased risk of liver cancer among the Chinese population (c2 vs. c1: OR = 0.70, 95%CI: 0.54-0.91, P = 0.007; c2/c2 + c2/c1 vs. c1/c1: OR = 0.72, 95%CI: 0.54-0.95, P = 0.020), but not among Japanese and Korean populations. Results from the current meta-analysis indicates that the c2 allele of CYP2E1 RsaI/PstI (c1/c2) polymorphism may be a protective factor for HCC among east Asians, especially among China populations.Asian Pacific journal of cancer prevention: APJCP 10/2012; 13(10):4915-21. DOI:10.7314/APJCP.2012.13.10.4915 · 1.50 Impact Factor
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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