Increased formation of gastric N2-ethylidene-2′-deoxyguanosine DNA adducts in aldehyde dehydrogenase-2 knockout mice treated with ethanol

Nagayoshi, Haruna; Matsumoto, Akiko; Nishi, Ryuhei; Kawamoto, Toshihiro; Ichiba, Masayoshi; Matsuda, Tomonari

doi:10.1016/j.mrgentox.2008.11.009

Cited by 50 publications

(39 citation statements)

References 30 publications

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“…The authors concluded that homologous recombination, translesion synthesis, and the Fanconi anaemia gene FANCD2 protected against formaldehyde-induced clonogenic cell killing. Numerous studies have reported that cells exposed to acetaldehyde accumulate DNA damage 10,11 . Moreover, ethanol exposure (a dietary source of acetaldehyde) in mice and humans results in DNA base damage [10][11][12][13] .…”

Section: Fanconi B Cells Are Sensitive To Acetaldehydementioning

confidence: 99%

“…Numerous studies have reported that cells exposed to acetaldehyde accumulate DNA damage 10,11 . Moreover, ethanol exposure (a dietary source of acetaldehyde) in mice and humans results in DNA base damage [10][11][12][13] . We compared the sensitivity of a chicken B-cell line, DT40, carrying a disruption of the Fanconi anaemia gene FANCL (DFANCL) to acetaldehyde, and found that this mutant strain is markedly sensitive to exogenous acetaldehyde (Fig.…”

Section: Fanconi B Cells Are Sensitive To Acetaldehydementioning

confidence: 99%

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Fancd2 counteracts the toxic effects of naturally produced aldehydes in mice

Langevin

Crossan

Rosado

et al. 2011

Nature

466

437

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Reactive aldehydes are common carcinogens. They are also by-products of several metabolic pathways and, without enzymatic catabolism, may accumulate and cause DNA damage. Ethanol, which is metabolised to acetaldehyde, is both carcinogenic and teratogenic in humans. Here we find that the Fanconi anaemia DNA repair pathway counteracts acetaldehyde-induced genotoxicity in mice. Our results show that the acetaldehyde-catabolising enzyme Aldh2 is essential for the development of Fancd2(-/-) embryos. Nevertheless, acetaldehyde-catabolism-competent mothers (Aldh2(+/-)) can support the development of double-mutant (Aldh2(-/-)Fancd2(-/-)) mice. However, these embryos are unusually sensitive to ethanol exposure in utero, and ethanol consumption by postnatal double-deficient mice rapidly precipitates bone marrow failure. Lastly, Aldh2(-/-)Fancd2(-/-) mice spontaneously develop acute leukaemia. Acetaldehyde-mediated DNA damage may critically contribute to the genesis of fetal alcohol syndrome in fetuses, as well as to abnormal development, haematopoietic failure and cancer predisposition in Fanconi anaemia patients.

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Section: Fanconi B Cells Are Sensitive To Acetaldehydementioning

confidence: 99%

Section: Fanconi B Cells Are Sensitive To Acetaldehydementioning

confidence: 99%

Fancd2 counteracts the toxic effects of naturally produced aldehydes in mice

Langevin

Crossan

Rosado

et al. 2011

Nature

466

437

View full text Add to dashboard Cite

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“…ALDH2 also appears to influence bone growth and cardiac function, as demonstrated by reductions in trabecular bone formation and cardiomyocyte function in Aldh2 −/− mice treated with alcohol [66, 67]. Stomach DNA adducts are dramatically increased after chronic ethanol feeding of Aldh2 −/− mice [68, 69] and acute ethanol treatment increases hepatic oxidative DNA adducts in null mice [70, 71]. The Aldh2 −/− strain represents a valuable strain that can be used to identify functions of ALDH2 in ethanol metabolism and toxicity.…”

Section: Mouse Models With Genetic Deficiencies In Acetaldehyde-mmentioning

confidence: 99%

Transgenic Mouse Models for Alcohol Metabolism, Toxicity, and Cancer

Heit

Dong

Chen

et al. 2014

Advances in Experimental Medicine and Biology

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Alcohol abuse leads to tissue damage including a variety of cancers; however, the molecular mechanisms by which this damage occurs remains to be fully understood. The primary enzymes involved in ethanol metabolism include alcohol dehydrogenase (ADH), cytochrome P450 isoform 2E1, (CYP2E1), catalase (CAT), and aldehyde dehydrogenases (ALDH). Genetic polymorphisms in human genes encoding these enzymes are associated with increased risks of alcohol-related tissue damage, as well as differences in alcohol consumption and dependence. Oxidative stress resulting from ethanol oxidation is one established pathogenic event in alcohol-induced toxicity. Ethanol metabolism generates free radicals, such as reactive oxygen species (ROS) and reactive nitrogen species (RNS), and has been associated with diminished glutathione (GSH) levels as well as changes in other antioxidant mechanisms. In addition, the formation of protein and DNA adducts associated with the accumulation of ethanol-derived aldehydes can adversely affect critical biological functions and thereby promote cellular and tissue pathology. Animal models have proven to be valuable tools for investigating mechanisms underlying pathogenesis caused by alcohol. In this review, we provide a brief discussion on several animal models with genetic defects in alcohol metabolizing enzymes and GSH synthesizing enzymes and their relevance to alcohol research.

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“…We previously reported that acetaldehyde-derived DNA adducts are elevated to a greater extent in the liver and stomach of Aldh2 knockout mice following ethanol administration than in the liver and stomach of wild type mice [49,50]. Similarly, Ishikawa and colleagues [51] showed that subjects carrying the ALDH2*2 allele who consumed ethanol more than three times per week had greater DNA damage, as reflected by an increased micronuclei frequency.…”

Section: Effect Of Aldh2*2 On Cancerous Diseasesmentioning

confidence: 89%