Characteristics of aldehyde dehydrogenase 2 (<i>Aldh2</i>) knockout mice

Yu, Huijuan; Oyama, Tsunehiro; Isse, Toyohi; Kitakawa, Kyoko; Ogawa, Masanori; Pham, Thi-Thu-Phuong; Kawamoto, Toshihiro

doi:10.3109/15376510903401708

Cited by 28 publications

(18 citation statements)

References 36 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Homozygous mice were born at the expected Mendelian ratios and show no overt phenotype ( Supplementary Fig. 3c), consistent with previously published Aldh2 knockout mice 23 . Second, we crossed Aldh2 2/2 with Fancd2 1/2 mice made in the 129S4 background 24 .…”

Section: Fanconi B Cells Are Sensitive To Acetaldehydesupporting

confidence: 87%

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

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.

show abstract

Section: Fanconi B Cells Are Sensitive To Acetaldehydesupporting

confidence: 87%

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

show abstract

“…This causes the "alcohol flushing" syndrome characterized by the reddening of the face, neck, and, in some cases, the entire body due to dilation of capillaries (Eriksson, 2001). Similar elevations in acetaldehyde have been observed in the Aldh2-null mice (Yu et al, 2009). The second enzyme involved in acetaldehyde metabolism is ALDH1A1.…”

Section: Introductionmentioning

confidence: 53%

“…Another study reported that the dynamic expression of ALDH1B1 correlated with granulocytic development of hematopoietic stem cells; in this report, the author proposed a possible role of ALDH1B1 in retinoic acid metabolism mediating the effect (Luo et al, 2007). A transgenic mouse line having forced expression of the human ALDH2*2 variant exhibited distinct phenotypes, including small body size, reduced muscle mass, diminished fat content, and osteopenia (Endo et al, 2009), all of which are absent from ALDH2-null mice (Yu et al, 2009). One hypothesis to explain such a discrepancy is that the ALDH2*2 mutant subunit not only inactivates the ALDH2 wild-type subunit but also inactivates other ALDHs by forming heterotetramers, thereby blocking their functions.…”

Section: Initial Characterization Of Human Aldh1b1mentioning

confidence: 99%

“…Male C57BL/6J wild-type mice (ϳ12 weeks old) were purchased from The Jackson Laboratory (Bar Harbor, Maine). Aldh2(Ϫ/Ϫ) knockout mice were obtained from Dr. T. K. Kawamoto's laboratory (Department of Environmental Health, School of Medicine, University of Occupational and Environmental Health, Yahatanishi-ku, Kitakyushu, Japan) (Yu et al, 2009) and maintained in the C57BL/6J background. Mice were euthanized by CO 2 inhalation followed by cervical dislocation.…”

Section: Methodsmentioning

confidence: 99%

See 1 more Smart Citation

Aldehyde Dehydrogenase 1B1: Molecular Cloning and Characterization of a Novel Mitochondrial Acetaldehyde-Metabolizing Enzyme

Stagos¹,

Chen²,

Brocker³

et al. 2010

Drug Metab Dispos

121

114

View full text Add to dashboard Cite

ABSTRACT:Ethanol-induced damage is largely attributed to its toxic metabolite, acetaldehyde. Clearance of acetaldehyde is achieved by its oxidation, primarily catalyzed by the mitochondrial class II aldehyde dehydrogenase (ALDH2). ALDH1B1 is another mitochondrial aldehyde dehydrogenase (ALDH) that shares 75% peptide sequence homology with ALDH2. Recent population studies in whites suggest a role for ALDH1B1 in ethanol metabolism. However, to date, no formal documentation of the biochemical properties of ALDH1B1 has been forthcoming. In this current study, we cloned and expressed human recombinant ALDH1B1 in Sf9 insect cells. The resultant enzyme was purified by affinity chromatography to homogeneity. The kinetic properties of purified human ALDH1B1 were assessed using a wide range of aldehyde substrates. Human ALDH1B1 had an exclusive preference for NAD ؉ as the cofactor and was catalytically active toward short-and medium-chain aliphatic aldehydes, aromatic aldehydes, and the products of lipid peroxidation, 4-hydroxynonenal and malondialdehyde. Most importantly, human ALDH1B1 exhibited an apparent K m of 55 M for acetaldehyde, making it the second low K m ALDH for metabolism of this substrate. The dehydrogenase activity of ALDH1B1 was sensitive to disulfiram inhibition, a feature also shared with ALDH2. The tissue distribution of ALDH1B1 in C57BL/6J mice and humans was examined by quantitative polymerase chain reaction, Western blotting, and immunohistochemical analysis. The highest expression occurred in the liver, followed by the intestinal tract, implying a potential physiological role for ALDH1B1 in these tissues. The current study is the first report on the expression, purification, and biochemical characterization of human ALDH1B1 protein.

show abstract

“…The closest model to the human ALDH2*2 polymorphism is the Aldh2 knockout (KO) mouse, which expresses no protein or enzymatic activity (20). Although Aldh2 KO mice are useful for investigating the impact of complete lack of ALDH2 activity (21), they fail to faithfully reproduce the structural and biochemical properties of ALDH2*2 in human physiology and pathology (21)(22)(23). In particular, ALDH2*2 is expressed with reduced but not loss of enzymatic activity and increased protein turnover (24).…”

mentioning

confidence: 99%

ALDH2(E487K) mutation increases protein turnover and promotes murine hepatocarcinogenesis

Jin

Chen

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

View full text Add to dashboard Cite

Mitochondrial aldehyde dehydrogenase 2 (ALDH2) in the liver removes toxic aldehydes including acetaldehyde, an intermediate of ethanol metabolism. Nearly 40% of East Asians inherit an inactive ALDH2*2 variant, which has a lysine-for-glutamate substitution at position 487 (E487K), and show a characteristic alcohol flush reaction after drinking and a higher risk for gastrointestinal cancers. Here we report the characterization of knockin mice in which the ALDH2(E487K) mutation is inserted into the endogenous murine Aldh2 locus. These mutants recapitulate essentially all human phenotypes including impaired clearance of acetaldehyde, increased sensitivity to acute or chronic alcohol-induced toxicity, and reduced ALDH2 expression due to a dominant-negative effect of the mutation. When treated with a chemical carcinogen, these mutants exhibit increased DNA damage response in hepatocytes, pronounced liver injury, and accelerated development of hepatocellular carcinoma (HCC). Importantly, ALDH2 protein levels are also significantly lower in patient HCC than in peritumor or normal liver tissues. Our results reveal that ALDH2 functions as a tumor suppressor by maintaining genomic stability in the liver, and the common human ALDH2 variant would present a significant risk factor for hepatocarcinogenesis. Our study suggests that the ALDH2*2 allele-alcohol interaction may be an even greater human public health hazard than previously appreciated. ALDH2*2 polymorphism | Asian flush | alcohol metabolism | mouse model | liver cancer M itochondrial aldehyde dehydrogenase 2 (ALDH2) is essential for alcohol detoxification. It is the second enzyme in the major oxidative pathway of alcohol metabolism, removing acetaldehyde (ACE), a toxic intermediate product from ethanol metabolism (1). More than 500 million people worldwide, mostly in East Asia, have a G-to-A point mutation in their ALDH2 gene (2, 3). This mutation results in a glutamic acid-to-lysine substitution at residue 487 (E487K) of the human ALDH2 protein (designated ALDH2*2). ALDH2*2 has significantly reduced ability to metabolize ACE (4, 5). Importantly, its activity is partially dominant-negative over that of the wild-type ALDH2*1, due to the structural alterations introduced by the mutation to the ALDH2 homotetramer complex (6). As a result, individuals with a heterozygous ALDH2*2/2*1 genotype have less than half the wild-type activity, and ALDH2*2/2*2 homozygotes have very low residual activity (7). Accumulated ACE can cause an alcohol flush reaction, commonly found in Asians with this variant after alcohol consumption (also called "Asian glow").ACE binds to cellular proteins and DNA, leading to DNA damage and organ injury (8). Specifically, endogenous aldehydes are detrimental to hematopoietic stem cells that are defective in Fanconi anemia DNA repair (9, 10). As a result, Fanconi anemia patients with the ALDH2*2 allele exhibit accelerated disease progression (11). ALDH2*2 can also increase the risk for gastrointestinal cancers, such as gastric carcinoma (12), esophagea...

show abstract

Characteristics of aldehyde dehydrogenase 2 (Aldh2) knockout mice

Cited by 28 publications

References 36 publications

Fancd2 counteracts the toxic effects of naturally produced aldehydes in mice

Fancd2 counteracts the toxic effects of naturally produced aldehydes in mice

Aldehyde Dehydrogenase 1B1: Molecular Cloning and Characterization of a Novel Mitochondrial Acetaldehyde-Metabolizing Enzyme

ALDH2(E487K) mutation increases protein turnover and promotes murine hepatocarcinogenesis

Contact Info

Product

Resources

About