Tissue-distribution of aldehyde dehydrogenase 2 and effects of the Aldh2 gene-disruption on the expression of enzymes involved in alcohol metabolism

Oyama, Tsunehiro; Isse, Toyohi; Kagawa, Norio; Kinaga, Tsuyoshi; Kim, Yong‐Dae; Morita, Masaru; Sugio, Kenji; Weiner, Henry; Yasumoto, Kosei; Kawamoto, Toshihiro

doi:10.2741/1589

Cited by 69 publications

(55 citation statements)

References 74 publications

(5 reference statements)

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“…The human ALDH2 gene is located on chromosome 12 and consists of 13 exons and 12 introns spanning approximately 44 kb [14,28,29]. The 517-amino acid gene product is expressed most abundantly in the liver and stomach, but is present in all tissues throughout the body [30]. The protein is posttranslationally processed and imported into the mitochondria of liver cells [22].…”

Section: Characterization Of Aldh2*2mentioning

confidence: 99%

Emerging Associations of the ALDH2*2 Polymorphism with Disease Susceptibility

Gueldner¹,

Sayes²,

Abel³

et al. 2016

J Drug Metab Toxicol

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Ethanol is metabolized by Alcohol Dehydrogenase (ADH) to acetaldehyde and then irreversibly oxidized by Aldehyde Dehydrogenase (ALDH) to nontoxic acetate. In individuals expressing the ALDH2*2 variant enzyme, the rate of conversion from acetaldehyde to acetate is reduced and leads to flushing, nausea, and tachycardia due to increased blood levels of acetaldehyde. The ALDH2*2 variant has a lowered NAD + coenzyme binding affinity, which results in a lowered clearance capacity toward acetaldehyde. This polymorphism is caused by the substitution of glutamate for lysine at position 487 within the catalytic active site of ALDH2, resulting in effects on subunit and quaternary complex activity. ALDH2*2 alleles are dominant over ALDH2*1 and therefore are expected to contribute to the formation of inactive heterotetramers decreased enzymatic activity in both homozygous and heterozygous individuals. Consequently, a higher susceptibility to various diseases such as Alzheimer's, osteoporosis, and acute coronary syndrome has been associated with ALDH2*2 carriers. Additionally, the polymorphism seems to affect the efficacy of Glyceryl Trinitrate (GTN), a drug intended to treat coronary heart disease, in carriers of ALDH2*2 alleles. However, the polymorphism is believed to afford a protective effect against alcoholism as the side effects of acetaldehyde build-up are undesirable. Disulfiram, a drug historically used to treat alcohol dependency, induces the same undesirable physiological effects as the variant enzyme in non-carriers by inhibiting the normal functioning of ALDH2 enzyme.

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Section: Characterization Of Aldh2*2mentioning

confidence: 99%

Emerging Associations of the ALDH2*2 Polymorphism with Disease Susceptibility

Gueldner¹,

Sayes²,

Abel³

et al. 2016

J Drug Metab Toxicol

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“…The number of Japanese alcoholism patients was about 2.5 million in 1995 and has been gradually increasing Oyama et al, 2005). Many epidemiological studies have consistently demonstrated that alcohol consumption is related to the development of various cancers and liver diseases, all of which are associated with altered levels of various intracellular oxidizing enzymes (Blum, 2001;Katoh et al, 1999;Novak and Woodcroft, 2000).…”

Section: Introductionmentioning

confidence: 99%

A Pirot Study on Subacute Ethanol Treatment of Aldh2 Ko Mice

et al. 2007

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-Aldh (aldehyde dehydrogenase ) 2 knockout (KO) mice have been generated in our laboratory. We evaluated the effects of subacute ethanol treatment on the survival rate, expression of Aldh1, Aldh2, Cytochrome P450 (Cyp) 1A1, Cyp2e1 and Cyp4b1 in wild (Aldh2 +/+) mice (C57BL/6) and Aldh2 knock out (Aldh2 −/−) mice. Physiological saline (0.3 mL/day) was administered to 4 Aldh2 +/+ and 4 Aldh2 −/− mice for 8 days as a control. Forty percent ethanol (0.3 mL/day; ethanol 2 g/kg/day) was then administered to 5 Aldh2 +/+ and 9 Aldh2 −/− mice for 8 days. Three mice of the ethanol administered Aldh2 +/+ group and eight mice of the ethanol administered Aldh2 −/− group died during the 8 days. The weights of mice were decreased by ethanol exposure to 85% and 74% in Aldh2 +/+ and Aldh2 −/− group, respectively. The survival rates of the ethanol administered Aldh2 +/+ and Aldh2 −/− group were 40 and 11%. Liver and pancreas disorder was revealed in the ethanol administered Aldh2 +/+ and Aldh2 −/− group in the results of serum chemical examination, immunohistochemical staining and western blot analysis. Cyp2e1 is more inducible to ethanol toxicity in Aldh2 −/− mice compared with Aldh2 +/+ mice when ethanol is administered according to the results of quantitative PCR.

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“…The column epithelium with cilia (bronchial epithelium) can be recognized by Papanicolaou staining. For CYP2A6 staining, a mouse monoclonal antibody (Daiichi Pure Chemicals Co., Ltd., Tokyo) was used as described previously (31).…”

Section: Cytochrome P450 Expression In Bronchial Epitheliummentioning

confidence: 99%

Evidence-based prevention (EBP): A review of cytochrome P450 expression in the bronchial epithelium and new approach to lung cancer prevention

Oyama

Isse

Murakami

et al. 2006

Environ. Health Prev. Med.

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The number of fatalities in Japan attributable to lung cancer exceeded 50000 in 2001. It is socially desirable that various markers, which can be utilized for the prevention of lung cancer, be established. We believe that smoking or exposure to carcinogens in air induces mutations in bronchial and alveolar epithelia, leading to the development of lung cancer. It would be useful to have markers of individual differences in susceptibility to chemical carcinogen-induced lung cancer 1) to identify genetic polymorphisms of enzymes metabolizing chemical carcinogens and 2) to investigate the expression of enzymes metabolizing chemical carcinogens. In this paper, we review CYP expression in the bronchial epithelium. CYP1, CYP2 and CYP3 are expressed in the bronchial epithelium. We also show the relationship between the genetic polymorphisms of cytochrome P450 (CYP) and a person's susceptibility to chemical carcinogen-induced lung cancer. We demonstrate the relationship between cigarette consumption and the CYP expression profile in the bronchial epithelium. To maintain and promote public health, we must apply evidence, such as CYP polymorphisms and CYP profiles to disease prevention and also to aggressively advance evidence-based prevention (EBP) of lung cancer.

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Tissue-distribution of aldehyde dehydrogenase 2 and effects of the Aldh2 gene-disruption on the expression of enzymes involved in alcohol metabolism

Cited by 69 publications

References 74 publications

Emerging Associations of the ALDH2*2 Polymorphism with Disease Susceptibility

Emerging Associations of the ALDH2*2 Polymorphism with Disease Susceptibility

A Pirot Study on Subacute Ethanol Treatment of Aldh2 Ko Mice

Evidence-based prevention (EBP): A review of cytochrome P450 expression in the bronchial epithelium and new approach to lung cancer prevention

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