Article

Increased Etheno-DNA Adducts in Affected Tissues of Patients Suffering from Crohn’s Disease, Ulcerative Colitis, and Chronic Pancreatitis

Division of Toxicology and Cancer Risk Factors, German Cancer Research Center, Heidelberg, Germany.
Antioxidants and Redox Signaling (Impact Factor: 7.41). 05/2006; 8(5-6):1003-10. DOI: 10.1089/ars.2006.8.1003
Source: PubMed

ABSTRACT

Chronic inflammatory processes induce oxidative stress and lipid peroxidation (LPO), hereby generating DNA-reactive aldehydes such as trans-4-hydroxy-2-nonenal (HNE). Etheno-modified DNA bases are inter alia generated by reaction of DNA with HNE. Using an immunoaffinity-(32)P-postlabeling method, the authors have investigated etheno-DNA adduct levels 1,N (6)-ethenodeoxyadenosine (epsilondA) and of 3,N (4)-ethenodeoxycytidine (epsilondC) in the pancreas of chronic pancreatitis patients and in the colon of patients with inflammatory bowel disease. Both epsilondA and epsilondC levels were found to be significantly, 3 and 28 times, respectively, elevated in the inflamed pancreatic tissue. In contrast, only epsilondC was found to be increased in affected colonic mucosa of Crohn's disease (19 times) and of ulcerative colitis patients (4 times) when compared to asymptomatic tissues. In all three cancer-prone diseases, the mean epsilondC-levels in tissues were five- to ninefold higher than those of epsilondA. Differential or impaired DNA repair pathways of these adducts, known to occur by two different glycosylases are implicated. K-ras in pancreatic tumors and K-ras and p53 in colon mucosa in long-standing inflammatory bowel disease are known to be highly mutated. The conclusion is that promutagenic etheno-DNA adducts are generated as a consequence of chronic inflammation, acting as a driving force to malignancy in cancer-prone inflammatory diseases.

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    • "Ethenoadducts have been implicated in the etiology of human cancer-promoting diseases. The levels of 1,N 6 -ethenoadenine (␧A) and 3,N 4 -ethenocytosine (␧C) are increased in Wilson disease [9], hemochromatosis [9], familial adenomatous polyposis [10], and Crohn's disease [11]. It has also been reported that adducts of 4- hydroxy-2-alkenals to DNA bases, but also to proteins, could be engaged in aging and neurodegeneration [12] [13]. "

    Full-text · Dataset · Nov 2014
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    • "Ethenoadducts have been implicated in the etiology of human cancer-promoting diseases. The levels of 1,N 6 -ethenoadenine (␧A) and 3,N 4 -ethenocytosine (␧C) are increased in Wilson disease [9], hemochromatosis [9], familial adenomatous polyposis [10], and Crohn's disease [11]. It has also been reported that adducts of 4- hydroxy-2-alkenals to DNA bases, but also to proteins, could be engaged in aging and neurodegeneration [12] [13]. "
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    ABSTRACT: Oxidative-stress-driven lipid peroxidation (LPO) is involved in the pathogenesis of several human diseases, including cancer. LPO products react with cellular proteins changing their properties, and with DNA bases to form mutagenic etheno-DNA adducts, removed from DNA mainly by the base excision repair (BER) pathway. One of the major reactive aldehydes generated by LPO is 4-hydroxy-2-nonenal (HNE). We investigated the effect of HNE on BER enzymes in human cells and in vitro. K21 cells pretreated with physiological HNE concentrations were more sensitive to oxidative and alkylating agents, H2O2 and MMS, than were untreated cells. Detailed examination of the effects of HNE on particular stages of BER in K21 cells revealed that HNE decreases the rate of excision of 1,N(6)-ethenoadenine (ɛA) and 3,N(4)-ethenocytosine (ɛC), but not of 8-oxoguanine. Simultaneously HNE increased the rate of AP-site incision and blocked the re-ligation step after the gap-filling by DNA polymerases. This suggested that HNE increases the number of unrepaired single-strand breaks (SSBs) in cells treated with oxidizing or methylating agents. Indeed, preincubation of cells with HNE and their subsequent treatment with H2O2 or MMS increased the number of nuclear poly(ADP-ribose) foci, known to appear in cells in response to SSBs. However, when purified BER enzymes were exposed to HNE, only ANPG and TDG glycosylases excising ɛA and ɛC from DNA were inhibited, and only at high HNE concentrations. APE1 endonuclease and 8-oxoG-DNA glycosylase 1 (OGG1) were not inhibited. These results indicate that LPO products exert their promutagenic action not only by forming DNA adducts, but in part also by compromising the BER pathway.
    Full-text · Article · Jul 2014 · DNA Repair
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    • "Chronic inflammation also induces lipid peroxidation that generates etheno-modified DNA bases. In tissue of patients suffering from Crohn's disease and ulcerative colitis, there is a 2-to 20- fold increase in the levels of promutagenic etheno-DNA adducts in the colon compared to those in controls (Nair et al., 2006). Infection of RAG2-deficient mice with Helicobacter hepaticus leads to the accumulation of macrophages and neutrophils in the colon, with increased nitric oxide (NO) production (Erdman et al., 2009). "
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    ABSTRACT: In recent years, our understanding of the mechanisms underlying colorectal carcinogenesis has vastly expanded. Underlying inflammation within the intestine, diet, and most recently, the gut microbiota, have been demonstrated to influence the development of colorectal cancer. However, since cancer is ultimately a genetic disease, these factors are thought to create genotoxic stress within the intestinal environment to promote genetic and epigenetic alterations leading to cancer. In this review, we will focus on how gut microbes intersect with inflammation, diet, and host genetics to influence the development of colon cancer.
    Full-text · Article · Apr 2014 · Molecular cell
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