Recovery from anemia and leukocytopenia after abstinence in Japanese alcoholic men and their genetic polymorphisms of alcohol dehydrogenase-1B and aldehyde dehydrogenase-2

Yokoyama, Akira; Brooks, Philip J.; Yokoyama, Tetsuji; Mizukami, Takeshi; Shiba, Shintaro; Nakamoto, Nobuhiro; Maruyama, Katsuya

doi:10.1093/jjco/hyw208

Cited by 11 publications

(7 citation statements)

References 31 publications

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“…The ALDH2*1/*2 genotype is a major determinant of high blood acetaldehyde exposure after alcohol intake. Although an ADH1B*2 genotype has little effect on blood acetaldehyde levels after alcohol challenge tests using moderate doses of ethanol in non-AD patients 48 , previous studies have suggested that blood acetaldehyde exposure is the highest in drinkers with the ALDH2*1/*2 and ADH1B*2 genotype combination for the following reasons: the slope of the increase in blood acetaldehyde levels according to the increase in blood ethanol levels were found to be steepest for intoxicated AD individuals belonging to this group 49 , the highest levels of N2-ethylidene-dG, an acetaldehyde-DNA adduct, were detected in the leukocytes of AD individuals belonging to this group 19 , and the most severe macrocytic anemia and leukocytopenia 50 and the slowest recoveries after the cessation of drinking 51 were observed among AD individuals belonging to this group, suggesting the strongest bone marrow suppression as a result of the highest blood acetaldehyde exposure. In contrast, the direct effect of acetaldehyde on the function of immune cells has not been elucidated to data.…”

Section: Discussionmentioning

confidence: 99%

Acetaldehyde exposure underlies functional defects in monocytes induced by excessive alcohol consumption

Shiba

Nakamoto

Chu

et al. 2021

Sci Rep

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Increased intestinal permeability and hepatic macrophage activation by endotoxins are involved in alcohol-induced liver injury pathogenesis. Long-term alcohol exposure conversely induces endotoxin immune tolerance; however, the precise mechanism and reversibility are unclear. Seventy-two alcohol-dependent patients with alcohol dehydrogenase-1B (ADH1B, rs1229984) and aldehyde dehydrogenase-2 (ALDH2, rs671) gene polymorphisms admitted for alcohol abstinence were enrolled. Blood and fecal samples were collected on admission and 4 weeks after alcohol cessation and were sequentially analyzed. Wild-type and ALDH2*2 transgenic mice were used to examine the effect of acetaldehyde exposure on liver immune responses. The productivity of inflammatory cytokines of peripheral CD14+ monocytes in response to LPS stimulation was significantly suppressed in alcohol dependent patients on admission relative to that in healthy controls, which was partially restored by alcohol abstinence with little impact on the gut microbiota composition. Notably, immune suppression was associated with ALDH2/ADH1B gene polymorphisms, and patients with a combination of ALDH2*1/*2 and ADH1B*2 genotypes, the most acetaldehyde-exposed group, demonstrated a deeply suppressed phenotype, suggesting a direct role of acetaldehyde. In vitro LPS and malondialdehyde-acetaldehyde adducted protein stimulation induced direct cytotoxicity on monocytes derived from healthy controls, and a second LPS stimulation suppressed the inflammatory cytokines production. Consistently, hepatic macrophages of ethanol-administered ALDH2*2 transgenic mice exhibited suppressed inflammatory cytokines production in response to LPS compared to that in wild-type mice, reinforcing the contribution of acetaldehyde to liver macrophage function. These results collectively provide new perspectives on the systemic influence of excessive alcohol consumption based on alcohol-metabolizing enzyme genetic polymorphisms.

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Section: Discussionmentioning

confidence: 99%

Acetaldehyde exposure underlies functional defects in monocytes induced by excessive alcohol consumption

Shiba

Nakamoto

Chu

et al. 2021

Sci Rep

Self Cite

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“…Hematological abnormalities such as anemia and leukocytopenia are a frequent complication of alcoholism even in normal individuals, 50 and individuals heterozygous for the ALDH2*2 allele who are alcoholics have increased susceptibility to these conditions. 51 In a study of Japanese men, heterozygous ALDH2*2 individuals who were moderate to heavy drinkers had lower red cell counts and hemoglobin levels than never or rare drinkers. 52 In addition, acetaldehyde causes DNA damage in hematopoietic stem cells, impairs blood production, and promotes bone marrow failure.…”

Section: Body Weight Hemoglobin Locomotion and Dermatological Abnomentioning

confidence: 99%

Systemic Adeno-Associated Virus-Mediated Gene Therapy Prevents the Multiorgan Disorders Associated with Aldehyde Dehydrogenase 2 Deficiency and Chronic Ethanol Ingestion

Matsumura

Alwaseem

et al. 2020

Human Gene Therapy

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{ These authors contributed equally as senior authors.Aldehyde dehydrogenase type 2 (ALDH2), a key enzyme in ethanol metabolism, processes toxic acetaldehyde to nontoxic acetate. ALDH2 deficiency affects 8% of the world population and 35-45% of East Asians. The ALDH2*2 allele common genetic variant has a glutamic acid-to-lysine substitution at position 487 (E487K) that reduces the oxidizing ability of the enzyme resulting in systemic accumulation of acetaldehyde with ethanol ingestion. With chronic ethanol ingestion, mutations in ALDH2 are associated with a variety of hematological, neurological, and dermatological abnormalities, and an increased risk for esophageal cancer and osteoporosis. Based on our prior studies demonstrating that a one-time administration of an adeno-associated virus (AAV) serotype rh.10 gene transfer vector expressing the human ALDH2 cDNA (AAVrh.10hALDH2) prevents the acute effects of ethanol administration (the ''Asian flush syndrome''), we hypothesized that AAVrh.10hALDH2 would also prevent the chronic disorders associated with ALDH2 deficiency and chronic ethanol ingestion. To assess this hypothesis, AAVrh.10hALDH2 (10 11 genome copies) was administered intravenously to two models of ALDH2 deficiency, Aldh2 knockout homozygous (Aldh2 -/-) and knockin homozygous (Aldh2 E487K+/+ ) mice (n = 10 per group). Four weeks after vector administration, mice were given drinking water with 10-15% ethanol for 12 weeks. Strikingly, compared with nonethanol drinking littermates, AAVrh.10hALDH2 administration prevented chronic ethanol-induced serum acetaldehyde accumulation and elevated liver malondialdehyde levels, loss of body weight, reduced hemoglobin levels, reduced performance in locomotor activity tests, accumulation of esophageal DNA damage and DNA adducts, and development of osteopenia. AAVrh.10hALDH2 should be considered as a preventative therapy for the increased risk of chronic disorders associated with ALDH2 deficiency and chronic alcohol exposure.

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“…Different sensitivity of laboratory markers in alcohol dependent patients is also influenced by other factors, which we were not able to control for in our study. Yokoyama et al [22] discovered the important role of genetic polymorphism of alcohol dehydrogenases in different MCV values among chronic drinkers. Sakutata [23] observed, that chronic consumers of spirits have significantly higher MCV and GGT values comparing to chronic drinkers of fermented spirits (35% vs. 16% for MCV; 38% vs. 27% for GGT).…”

Section: ■ Discussionmentioning

confidence: 99%

Prevalence of gamma-glutamyltransferase and mean corpuscular volume laboratory markers in alcohol dependent patients

Okruhlica¹,

Kamendy²

2018

ain

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Recovery from anemia and leukocytopenia after abstinence in Japanese alcoholic men and their genetic polymorphisms of alcohol dehydrogenase-1B and aldehyde dehydrogenase-2

Abstract: Drinking cessation before surgery and/or chemoradiation treatment for esophageal cancer may be effective for recovery from anemia and leukocytopenia in drinkers belonging to the D group.

Cited by 11 publications

References 31 publications

Acetaldehyde exposure underlies functional defects in monocytes induced by excessive alcohol consumption

Acetaldehyde exposure underlies functional defects in monocytes induced by excessive alcohol consumption

Systemic Adeno-Associated Virus-Mediated Gene Therapy Prevents the Multiorgan Disorders Associated with Aldehyde Dehydrogenase 2 Deficiency and Chronic Ethanol Ingestion

Prevalence of gamma-glutamyltransferase and mean corpuscular volume laboratory markers in alcohol dependent patients

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