Aldehyde dehydrogenase 2 polymorphism is associated with chemotherapy‐related cognitive impairment in patients with breast cancer who receive chemotherapy
Senbang YaoWen LiShaochun LiuYinlian CaiQianqian ZhangLingxue TangSheng YuYanyan JingXiangxiang YinHuaidong Cheng
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Abstract Background Chemotherapy‐related cognitive impairment (CRCI) is a common but easily overlooked condition that markedly affects the quality of life (QOL) of patients with breast cancer. The rs671 is a common gene polymorphism of aldehyde dehydrogenase 2 ( ALDH2 ) in Asia that is involved in aldehyde metabolism and may be closely related to CRCI. However, no study has yet summarised the association between ALDH2 and CRCI. Methods This study enrolled one hundred and twenty‐four patients diagnosed with breast cancer according to the pathology results, genotyped for ALDH2 single‐nucleotide polymorphisms (SNP) to explore these. The mini‐mental state exam (MMSE), verbal fluency test (VFT), and digit span test (DST) results were compared in these patients before and after chemotherapy (CT). Results We found that patients with ALDH2 gene genotypes of rs671_GG, rs886205_GG, rs4648328_CC, and rs4767944_TT polymorphisms were more likely to suffer from cognitive impairment during chemotherapy. A trend toward statistical significance was observed for rs671_GG of DST (z = 2.769, p = 0.006), VFT ( t = 4.624, P<0.001); rs886205_GG of DST (z = 3.663, P<0.001); rs4648328_CC of DST (z = 2.850, p = 0.004), VFT ( t = 3.477, p = 0.001); and rs4767944_TT of DST (z = 2.967, p = 0.003), VFT ( t = 2.776, p = 0.008). The cognitive indicators of these patients significantly decreased after chemotherapy ( p < 0.05). The difference in ALDH2 rs671 was most obvious. Conclusion Our results showed what kinds of ALDH2 genotyped patients that are more likely to develop CRCI. In the future, it may be possible to infer the risk of CRCI by detecting the single‐nucleotide locus of ALDH2 that is conducive to strengthening clinical interventions for these patients and improving their QOL. More importantly, this study has important implications for Asian women with breast cancer as ALDH2 rs671 is a common polymorphism in Asians.Keywords:
ALDH2
The important enzymes for alcohol metabolism include alcohol dehydrogenase(ADH) and aldehyde dehydrogenase(ALDH) in human body.ALDH2 has the important role in the effect of aldehyde detoxification which is always the outcome in alcohol metabolism.At present,the studies on the structure and the polymorphism of gene ALDH2 and the expression of ALDH2 mRNA have made great progress.This paper will review the focuses.
ALDH2
Ethanol metabolism
ADH1B
Detoxification
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ALDH2
Phosphoglycerate mutase
Ethanol metabolism
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Genotypes of alcohol dehydrogenase (ADH) and aldehyde dehydrogenase (ALDH) loci were determined, using allele specific oligonucleotides. Gene frequencies of ADH2(1) and ADH2(2) were 0.29 and 0.71, respectively, in the Japanese control group. No significant difference was found in the ADH2 genotype between the patients and the control group. Gene frequency of ALDH2(1) and ALDH2(2) were 0.65 and 0.35 in the control group, while 0.93 and 0.07, respectively in the patient group. Most of the patients, 20 out of 23, were homozygous Caucasian type. All individuals with homozygous atypical ALDH2(2)/ALDH2(2) and most of those with heterozygous atypical ALDH2(1)/ALDH2(1) were alcohol flushers, while all of the usual ALDH2(1)/ALDH2(1) were nonflushers. The results indicate that Japanese with the atypical ALDH2(2) allele are at a much lower risk in developing alcoholic liver disease than those with usual ALDH2(1)/ALDH2(1), presumably due to their sensitivity to alcohol intoxication.
ALDH2
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Aldehyde dehydrogenase 2 (ALDH2) plays an important role in the cellular defense against toxic aldehydes for its ability to catalyze the oxidation of various aliphatic and aromatic aldehyde to the corresponding acids. It was reported that a high-frequency of mutant aldh2 allele (aldh2*2) existed in Asian population and the inherited deficiency of aldh2 may be the cause of the flushing syndrome and the uncomfortable effects of drinking alcohol. In this experiment, we successfully expressed ALDH2 and ALDH2*2, and identified the enzymatic activity of the two products for acetaldehyde. Their K_ms were 1.70μmol/L and 61.56 μmol/L respectively. This result supports the previous conclusion that the inherited deficiency of aldh2 is associated with the flushing syndrome and uncomfortable effects of drinking alcohol.
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Summary Although mitochondrial aldehyde dehydrogenase (ALDH2) has been thought to play a major role in acetaldehyde detoxification, and the high incidence of ‘alcohol flushing’ among Orientals is attributed to the inherited deficiency of ALDH2, the role of cytosolic aldehyde dehydrogenase (ALDH1) cannot be ignored. On the premise that alcohol flushing in Caucasians could be related to ALDH1 abnormalities, we examined the enzyme properties and electrophoretic mobilities of ALDH1 partially purified from red blood cells of nine unrelated alcohol flushers. One exhibited very low activity (10–20% of control level), and another exhibited moderately low activity (60%) and altered kinetic properties. The electrophoretic mobilities of these two samples were also distinguishable from the control samples. Immunological quantitation indicated that the amounts of ALDH1 protein in these two samples were not reduced in parallel with their enzyme deficiency. In the first case, the two characteristics, i.e. very low enzyme activity and alcohol flushing, were inherited by her daughter.
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Previously, we created an aldehyde dehydrogenase 2 gene transgenic (Aldh2-/-) mouse as an aldehyde dehydrogenase (ALDH) 2 inactive human model and demonstrated low alcohol preference. In addition, after a free-choice drinking test, no difference in the acetaldehyde level was observed between the Aldh2-/- and wild type (Aldh2+/+) mice. The actual amounts of free-choice drinking were so low that it is uncertain whether these levels are pharmacologically and/or behaviorally relevant in either strain. To elucidate this uncertainty, we compared the ethanol and acetaldehyde concentration in the blood, brain, and liver between the Aldh2-/- and Aldh2+/+ mice after ethanol gavages at the same dose and time.We measured differences in the ethanol and acetaldehyde levels between the Aldh2-/- and Aldh2+/+ mice by headspace gas chromatography-mass spectrometry (GC-MS) after ethanol gavages at the same dose and time.Significantly higher blood acetaldehyde concentrations were found in the Aldh2-/- mice than in the Aldh2+/+ mice 1 hr after the administration of ethanol gavages at doses of 0.5, 1.0, 2.0, and 5.0 g/kg. The blood acetaldehyde concentrations in the two strains were 2.4 vs. 0.5, 17.8 vs. 1.9, 108.3 vs. 4.3, and 247.2 vs. 14.0 (microM), respectively. In contrast, no significant difference was observed in the blood ethanol concentrations between the Aldh2+/+ and Aldh2-/- mice. The aldehyde dehydrogenase 2 enzyme metabolized 94% of the acetaldehyde produced from the ethanol as calculated from the area under the curve (AUC) of acetaldehyde when ethanol was administered at a dose of 5.0 g/kg.These data indicate that mouse ALDH2 is a major enzyme for acetaldehyde metabolism, and the Aldh2-/- mice have significantly high acetaldehyde levels after ethanol gavages.
ALDH2
Ethanol metabolism
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Human aldehyde dehydrogenase 1 (ALDH1A1) functions as an important enzyme in both the metabolism of acetaldehyde and the synthesis of retinoic acid (Elizondo et al., 2000; Ueshima et al., 1993). ALDH1A1 also has been implicated in several alcohol-related phenotypes, including alcoholism, alcohol-induced flushing, and alcohol sensitivity (Chan, 1986; Yoshida, 1992). Studies suggest that low ALDH1A1 activity may contribute to alcohol sensitivity and alcohol-induced flushing in Caucasians and some Asians (Ward et al., 1994; Yoshida et al., 1989). Adverse reactions resulting from reduced ALDH1A1 function may be influencing the predisposition for alcoholism in non-Asian populations (Eriksson, 2001). In fact, a study has identified a polymorphism in the coding region of ALDH1A1 that contributes to ethanol preference in high alcohol-preferring (HAP)/low alcohol-preferring (LAP) rats, suggesting that a functionally altered ALDH1A1 influences alcohol consumption in an animal model (Negoro et al., 1997; Nishiguchi et al., 2002). Due to its involvement in ethanol metabolism, ALDH1A1 is an interesting candidate for alcohol research.
Multiple aldehyde dehydrogenase isozymes have been characterized that exhibit similar functional properties implicated in ethanol detoxification, including ALDH1A1, ALDH1B1, ALDH2, and ALDH3A1 (Vasiliou and Pappa, 2000; Yoshida, 1992). The mitochondrial form of aldehyde dehydrogenase, or ALDH2, has been associated with a reduced incidence of alcoholism in certain Asian populations (Higuchi et al., 1995). In these populations, a functional polymorphism in ALDH2 leads to acetaldehyde accumulation, resulting in alcohol-induced flushing (Takeshita et al., 1994), but the underlying mechanism influencing alcoholic predisposition is still unknown (Li, 1997). The ALDH2 enzyme exhibits a higher affinity for acetaldehyde and primarily oxidizes acetaldehyde in humans (Klyosov et al., 1996); however, the functions of the ALDH isozymes in the central nervous system remain unclear (Stewart et al., 1996; Tank et al., 1986).
The promoter region contains regulatory binding sites that are involved in gene expression and tissue specificity (Mitchell and Tjian, 1989). Mutations in regulatory binding sites can substantially affect gene regulation, altering enzyme levels that can ultimately contribute to phenotypic variability throughout a population. Polymorphism in the ALDH1A1 promoter region could affect the steady-state levels of ALDH1A1 and alter acetaldehyde and retinoid metabolism. Thus far, variants of the regulatory region in the promoter of the ALDH1A1 gene have not yet been studied.
Although previous studies indicate that ALDH1A1 may contribute to alcoholism, alcohol sensitivity, and alcohol-induced flushing, no definitive evidence has been provided to adequately link ALDH1A1 to these phenotypes. The purpose of this study was to identify human ALDH1A1 promoter polymorphisms, to determine their functional significance, and to screen for associations between these polymorphisms and alcoholism.
ALDH2
Ethanol metabolism
Alcohol Dependence
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The important enzymes for alcohol metabolism included alcohol dehydrogenase (ADH) and aldehyde dehydrogenase (ALDH). The metabolic pathways of alcohol were as follows: alcohol oxidized into aldehyde, and then aldehyde oxidized into acetic acid. The genetic polymorphism of ADH was composed of ADH1,ADH2(1),ADH2(2)?ADH2(3),ADH3(1)and ADH3(2). The genetic polymorphism of ALDH was composed of ALDH1,ALDH2,ALDH3 and ALDH4.
ALDH2
Ethanol metabolism
ADH1B
Alcohol Oxidation
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We examined the genotypes of the aldehyde dehydrogenase (ALDH)‐2 , alcohol dehydrogenase (ADH)‐2, ADH3 , and P‐4502E1 loci of 53 alcoholics and 97 nonalcoholics. All of the subjects fulfilled the DSM‐III‐R criteria for alcohol dependence. The control group consisted of 97 subjects who were either hospital staff or students. We also compared the frequencies of homozygous ALDH2*1/1 and heterozygous ALDH2*1/2 genotypes in alcoholics. Our study revealed differences in the allelic frequencies of the ALDH2, ADH2 , and ADH3 loci between alcoholics and nonalcoholics. For alcoholics with both homozygous ALDH2*1/1 and heterozygous ALDH2*1/2 genotypes, it was found that ADH2 and ADH3 played important roles. Alcoholics with the heterozygous ALDH2*1/2 genotype showed a significantly higher frequency of ADH2*1/1 than ones with the homozygous ALDH2*1/1 genotype. We assume ADH2*1 plays an important role in the development of alcoholism in alcoholics with the heterozygous ALDH2*1/2 genotype.
ALDH2
Heterozygote advantage
Compound heterozygosity
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Abstract Background Only a subset of patients with excessive alcohol use develop alcoholic liver disease (ALD), though the exact mechanism is not completely understood. Once ingested, alcohol is metabolized by 2 key oxidative enzymes, alcohol dehydrogenase (ADH) and aldehyde dehydrogenase (ALDH). There are 2 major ALDH isoforms, cytosolic and mitochondrial, encoded by the aldehyde ALDH1 and ALDH2 genes, respectively. The ALDH2 gene was hypothesized to alter genetic susceptibility to alcohol dependence and alcohol-induced liver diseases. The aim of this study is to determine the association between aldehyde dehydrogenase 2 (rs671) glu504lys polymorphism and ALD. Methods ALDH2 genotyping was performed in 535 healthy controls and 281 patients with ALD. Results The prevalence of the common form of the single nucleotide polymorphism rs671, 504glu (glu/glu) was significantly higher in patients with ALD (95.4%) compared to that of controls (73.7%, P Conclusions Patients with ALDH2 504lys variant were less associated with ALD compared to those with ALDH2 504glu using both genotypic and allelic analyses.
ALDH2
Ethanol metabolism
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