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1.  Characterization of the East Asian Variant of Aldehyde Dehydrogenase-2 
The Journal of Biological Chemistry  2009;285(2):943-952.
The East Asian variant of mitochondrial aldehyde dehydrogenase (ALDH2) exhibits significantly reduced dehydrogenase, esterase, and nitroglycerin (GTN) denitrating activities. The small molecule Alda-1 was reported to partly restore low acetaldehyde dehydrogenase activity of this variant. In the present study we compared the wild type enzyme (ALDH2*1) with the Asian variant (ALDH2*2) regarding GTN bioactivation and the effects of Alda-1. Alda-1 increased acetaldehyde oxidation by ALDH2*1 and ALDH2*2 approximately 1.5- and 6-fold, respectively, and stimulated the esterase activities of both enzymes to similar extent as the coenzyme NAD. The effect of NAD was biphasic with pronounced inhibition occurring at ≥5 mm. In the presence of 1 mm NAD, Alda-1 stimulated ALDH2*2-catalyzed ester hydrolysis 73-fold, whereas the NAD-stimulated activity of ALDH2*1 was inhibited because of 20-fold increased inhibitory potency of NAD in the presence of the drug. Although ALDH2*2 exhibited 7-fold lower GTN denitrating activity and GTN affinity than ALDH2*1, the rate of nitric oxide formation was only reduced 2-fold, and soluble guanylate cyclase (sGC) activation was more pronounced than with wild type ALDH2 at saturating GTN. Alda-1 caused slight inhibition of GTN denitration and did not increase GTN-induced sGC activation in the presence of either variant. The present results indicate that Alda-1 stimulates established ALDH2 activities by improving NAD binding but does not improve the GTN binding affinity of the Asian variant. In addition, our data revealed an unexpected discrepancy between GTN reductase activity and sGC activation, suggesting that GTN denitration and bioactivation may reflect independent pathways of ALDH2-catalyzed GTN biotransformation.
doi:10.1074/jbc.M109.014548
PMCID: PMC2801295  PMID: 19906643
Cyclic GMP (cGMP); Enzyme Catalysis; Nitric Oxide; Oxidase; Superoxide Dismutase (SOD); Superoxide Ion; Bioactivation; Nitroglycerin
2.  Aldehyde dehydrogenase-2 regulates nociception in rodent models of acute inflammatory pain 
Science translational medicine  2014;6(251):251ra118.
Exogenous aldehydes can cause pain in animal models, suggesting that aldehyde dehydrogenase 2 (ALDH2), which metabolizes many aldehydes, may regulate nociception. To test this hypothesis, we generated a knock-in mouse with an inactivating point mutation in ALDH2 (ALDH2*2), which is also present in human ALDH2 of ~540 million East Asians. The ALDH2*1/*2 heterozygotic mice exhibited a larger response to painful stimuli than their wild-type littermates, and this heightened nociception was inhibited by an ALDH2-selective activator (Alda-1). No effect on inflammation per se was observed. Using a rat model, we then showed that nociception tightly correlated with ALDH activity (R2=0.90) and that reduced nociception was associated with less early growth response protein 1 (EGR1) in the spinal cord and less reactive aldehyde accumulation at the insult site (including acetaldehyde and 4-hydroxynonenal). Further, acetaldehyde and formalin-induced nociceptive behavior was greater in the ALDH2*1/*2 mice than wild-type mice. Finally, Alda-1 treatment was also beneficial when given even after the inflammatory agent was administered. Our data in rodent models suggest that the mitochondrial enzyme ALDH2 regulates nociception and could serve as a molecular target for pain control, with ALDH2 activators, such as Alda-1, as potential non-narcotic cardiac-safe analgesics. Furthermore, our results suggest a possible genetic basis for East Asians’ apparent lower pain tolerance.
doi:10.1126/scitranslmed.3009539
PMCID: PMC4234033  PMID: 25163478
3.  Activation of aldehyde dehydrogenase 2 (ALDH2) confers cardioprotection in protein kinase C epsilon (PKCε) knockout mice 
Acute administration of ethanol can reduce cardiac ischemia/reperfusion injury. Previous studies demonstrated that the acute cytoprotective effect of ethanol on the myocardium is mediated by protein kinase C epsilon (PKCε). We recently identified aldehyde dehydrogenase 2 (ALDH2) as an PKCε substrate, whose activation is necessary and sufficient to confer cardioprotection in vivo. ALDH2 metabolizes cytotoxic reactive aldehydes, such as 4-hydroxy-2-nonenal (4-HNE), which accumulate during cardiac ischemia/reperfusion. Here, we used a combination of PKCε knockout mice and a direct activator of ALDH2, Alda-44, to further investigate the interplay between PKCε and ALDH2 in cardioprotection. We report that ethanol preconditioning requires PKCε, whereas direct activation of ALDH2 reduces infarct size in both wild type and PKCε knockout hearts. Our data suggest that ALDH2 is downstream of PKCε in ethanol preconditioning and that direct activation of ALDH2 can circumvent the requirement of PKCε to induce cytoprotection. We also report that in addition to ALDH2 activation, Alda-44 prevents 4-HNE induced inactivation of ALDH2 by reducing the formation of 4-HNE-ALDH2 protein adducts. Thus, Alda-44 promotes metabolism of cytotoxic reactive aldehydes that accumulate in ischemic myocardium. Taken together, our findings suggest that direct activation of ALDH2 may represent a method of harnessing the cardioprotective effect of ethanol without the side effects associated with alcohol consumption.
doi:10.1016/j.yjmcc.2009.10.030
PMCID: PMC2837767  PMID: 19913552
4.  Alcohol Intake and Blood Pressure: A Systematic Review Implementing a Mendelian Randomization Approach 
PLoS Medicine  2008;5(3):e52.
Background
Alcohol has been reported to be a common and modifiable risk factor for hypertension. However, observational studies are subject to confounding by other behavioural and sociodemographic factors, while clinical trials are difficult to implement and have limited follow-up time. Mendelian randomization can provide robust evidence on the nature of this association by use of a common polymorphism in aldehyde dehydrogenase 2 (ALDH2) as a surrogate for measuring alcohol consumption. ALDH2 encodes a major enzyme involved in alcohol metabolism. Individuals homozygous for the null variant (*2*2) experience adverse symptoms when drinking alcohol and consequently drink considerably less alcohol than wild-type homozygotes (*1*1) or heterozygotes. We hypothesise that this polymorphism may influence the risk of hypertension by affecting alcohol drinking behaviour.
Methods and Findings
We carried out fixed effect meta-analyses of the ALDH2 genotype with blood pressure (five studies, n = 7,658) and hypertension (three studies, n = 4,219) using studies identified via systematic review. In males, we obtained an overall odds ratio of 2.42 (95% confidence interval [CI] 1.66–3.55, p = 4.8 × 10−6) for hypertension comparing *1*1 with *2*2 homozygotes and an odds ratio of 1.72 (95% CI 1.17–2.52, p = 0.006) comparing heterozygotes (surrogate for moderate drinkers) with *2*2 homozygotes. Systolic blood pressure was 7.44 mmHg (95% CI 5.39–9.49, p = 1.1 × 10−12) greater among *1*1 than among *2*2 homozygotes, and 4.24 mmHg (95% CI 2.18–6.31, p = 0.00005) greater among heterozygotes than among *2*2 homozygotes.
Conclusions
These findings support the hypothesis that alcohol intake has a marked effect on blood pressure and the risk of hypertension.
Using a mendelian randomization approach Sarah Lewis and colleagues find strong support for the hypothesis that alcohol intake has a marked effect on blood pressure and the risk of hypertension.
Editors' Summary
Background.
High blood pressure (hypertension) is a common medical condition that affects nearly a third of US and UK adults. Hypertension has no symptoms but can lead to heart attacks or strokes. It is diagnosed by measuring blood pressure—the force that blood moving around the body exerts on the inside of large blood vessels. Blood pressure is highest when the heart is pumping out blood (systolic pressure) and lowest when it is filling up with blood (diastolic pressure). Normal blood pressure is defined as a systolic pressure of less than 130 millimeters of mercury (mmHg) and a diastolic pressure of less than 85 mmHg (a blood pressure of 130/85). A reading of more than 140/90 indicates hypertension. Many factors affect blood pressure, but overweight people and individuals who eat too much salty or fatty foods are at high risk of developing hypertension. Mild hypertension can often be corrected by lifestyle changes, but many people also take antihypertensive drugs to reduce their blood pressure.
Why Was This Study Done?
Another modifiable lifestyle factor thought to affect blood pressure is alcohol intake. Observational studies that ask people about their drinking habits and measure their blood pressure suggest that alcohol intake correlates with blood pressure, but they cannot prove a causal link because of “confounding”—other risk factors associated with alcohol drinking, such as diet, might also affect the study participant's blood pressures. A trial that randomly assigns people to different alcohol intakes could provide this proof of causality, but such a trial is impractical. In this study, therefore, the researchers have used “Mendelian randomization” to investigate whether alcohol intake affects blood pressure. An inactive variant of aldehyde dehydrogenase 2 (ALDH2; the enzyme that removes alcohol from the body) has been identified. People who inherit the variant form of this gene from both parents have an ALDH2 *2*2 genotype (genetic makeup) and become flushed and nauseated after drinking. Consequently, they drink less than people with a *1*2 genotype and much less than those with a *1*1 genotype. Because inheritance of these genetic variants does not affect lifestyle factors other than alcohol intake, an association between ALDH2 genotypes and blood pressure would indicate that alcohol intake has an effect on blood pressure without any confounding.
What Did the Researchers Do and Find?
The researchers identified ten published studies (mainly done in Japan where the ALDH2 gene variant is common) on associations between ALDH2 genotype and blood pressure or hypertension using a detailed search protocol (a “systematic review”). A meta-analysis (a statistical method for combining the results of independent studies) of the studies that had investigated the association between ALDH2 genotype and hypertension showed that men with the *1*1 genotype (highest alcohol intake) and those with the *1*2 genotype (intermediate alcohol intake) were 2.42 and 1.72 times more likely, respectively, to have hypertension than those with the *2*2 genotype (lowest alcohol intake). There was no association between ALDH2 genotype and hypertension among the women in these studies because they drank very little. Systolic and diastolic blood pressures showed a similar relationship to ALDH2 genotype in a second meta-analysis of relevant studies. Finally, the researchers estimated that for men the lifetime effect of drinking 1 g of alcohol a day (one unit of alcohol contains 8 g of alcohol in the UK and 14 g in the US; recommended daily limits in these countries are 3–4 and 1–2 units, respectively) would be an increase in systolic blood pressure of 0.24 mmHg.
What Do These Findings Mean?
These findings support the suggestion that alcohol has a marked effect on blood pressure and hypertension. Consequently, some cases of hypertension could be prevented by encouraging people to reduce their daily alcohol intake. Although the Mendelian randomization approach avoids most of the confounding intrinsic to observational studies, it is possible that a gene near ALDH2 that has no effect on alcohol intake affects blood pressure, since genes are often inherited in blocks. Alternatively, ALDH2 could affect blood pressure independent of alcohol intake. The possibility that ALDH2 could effect blood pressure independently of alcohol is intake made unlikely by the fact that no effect of genotype on blood pressure is seen among women who drink very little. Additional large-scale studies are needed to address these possibilities, to confirm the current finding in more people, and to improve the estimates of the effect that alcohol intake has on blood pressure.
Additional Information.
Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.0050052.
The MedlinePlus encyclopedia has a page on hypertension (in English and Spanish)
The American Heart Association provides information for patients and health professionals about hypertension
The UK Blood Pressure Association provides information for patients and health professionals on all aspects of hypertension, including information about alcohol affects blood pressure
The Explore@Bristol science center (a UK charity) provides an alcohol unit calculator and information on the effects of alcohol
The International Center for Alcohol Policies provides drinking guidelines for countries around the world
doi:10.1371/journal.pmed.0050052
PMCID: PMC2265305  PMID: 18318597
5.  Neurodegeneration and Motor Dysfunction in Mice Lacking Cytosolic and Mitochondrial Aldehyde Dehydrogenases: Implications for Parkinson's Disease 
PLoS ONE  2012;7(2):e31522.
Previous studies have reported elevated levels of biogenic aldehydes in the brains of patients with Parkinson's disease (PD). In the brain, aldehydes are primarily detoxified by aldehyde dehydrogenases (ALDH). Reduced ALDH1 expression in surviving midbrain dopamine neurons has been reported in brains of patients who died with PD. In addition, impaired complex I activity, which is well documented in PD, reduces the availability of the NAD+ co-factor required by multiple ALDH isoforms to catalyze the removal of biogenic aldehydes. We hypothesized that chronically decreased function of multiple aldehyde dehydrogenases consequent to exposure to environmental toxins and/or reduced ALDH expression, plays an important role in the pathophysiology of PD. To address this hypothesis, we generated mice null for Aldh1a1 and Aldh2, the two isoforms known to be expressed in substantia nigra dopamine neurons. Aldh1a1−/−×Aldh2−/− mice exhibited age-dependent deficits in motor performance assessed by gait analysis and by performance on an accelerating rotarod. Intraperitoneal administration of L-DOPA plus benserazide alleviated the deficits in motor performance. We observed a significant loss of neurons immunoreactive for tyrosine hydroxylase (TH) in the substantia nigra and a reduction of dopamine and metabolites in the striatum of Aldh1a1−/−×Aldh2−/− mice. We also observed significant increases in biogenic aldehydes reported to be neurotoxic, including 4-hydroxynonenal (4-HNE) and the aldehyde intermediate of dopamine metabolism, 3,4-dihydroxyphenylacetaldehyde (DOPAL). These results support the hypothesis that impaired detoxification of biogenic aldehydes may be important in the pathophysiology of PD and suggest that Aldh1a1−/−×Aldh2−/− mice may be a useful animal model of PD.
doi:10.1371/journal.pone.0031522
PMCID: PMC3284575  PMID: 22384032
6.  Aldehyde dehydrogenase 2 in cardiac protection: a new therapeutic target? 
Trends in cardiovascular medicine  2009;19(5):158-164.
Mitochondrial aldehyde dehydrogenase 2 (ALDH2) is emerging as a key enzyme involved in cytoprotection in the heart. ALDH2 mediates both the detoxification of reactive aldehydes such as acetaldehyde and 4-hydroxy-2-nonenal (4-HNE) and the bioactivation of nitroglycerin (GTN) to nitric oxide (NO). In addition, chronic nitrate treatment results in ALDH2 inhibition and contributes to nitrate tolerance. Our lab recently identified ALDH2 to be a key mediator of endogenous cytoprotection. We reported that ALDH2 is phosphorylated and activated by the survival kinase protein kinase C epsilon (PKCε) and found a strong inverse correlation between ALDH2 activity and infarct size. We also identified a small molecule ALDH2 activator (Alda-1) which reduces myocardial infarct size induced by ischemia/reperfusion in vivo. In this review, we discuss evidence that ALDH2 is a key mediator of endogenous survival signaling in the heart, suggest possible cardioprotective mechanisms mediated by ALDH2, and discuss potential clinical implications of these findings.
doi:10.1016/j.tcm.2009.09.003
PMCID: PMC2856486  PMID: 20005475
7.  Molecular Cloning, Characterization, and Potential Roles of Cytosolic and Mitochondrial Aldehyde Dehydrogenases in Ethanol Metabolism in Saccharomyces cerevisiae† 
Journal of Bacteriology  1998;180(4):822-830.
The full-length DNAs for two Saccharomyces cerevisiae aldehyde dehydrogenase (ALDH) genes were cloned and expressed in Escherichia coli. A 2,744-bp DNA fragment contained an open reading frame encoding cytosolic ALDH1, with 500 amino acids, which was located on chromosome XVI. A 2,661-bp DNA fragment contained an open reading frame encoding mitochondrial ALDH5, with 519 amino acids, of which the N-terminal 23 amino acids were identified as the putative leader sequence. The ALDH5 gene was located on chromosome V. The commercial ALDH (designated ALDH2) was partially sequenced and appears to be a mitochondrial enzyme encoded by a gene located on chromosome XV. The recombinant ALDH1 enzyme was found to be essentially NADP dependent, while the ALDH5 enzyme could utilize either NADP or NAD as a cofactor. The activity of ALDH1 was stimulated two- to fourfold by divalent cations but was unaffected by K+ ions. In contrast, the activity of ALDH5 increased in the presence of K+ ions: 15-fold with NADP and 40-fold with NAD, respectively. Activity staining of isoelectric focusing gels showed that cytosolic ALDH1 contributed 30 to 70% of the overall activity, depending on the cofactor used, while mitochondrial ALDH2 contributed the rest. Neither ALDH5 nor the other ALDH-like proteins identified from the genomic sequence contributed to the in vitro oxidation of acetaldehyde. To evaluate the physiological roles of these three ALDH isoenzymes, the genes encoding cytosolic ALDH1 and mitochondrial ALDH2 and ALDH5 were disrupted in the genome of strain TWY397 separately or simultaneously. The growth of single-disruption Δald1 and Δald2 strains on ethanol was marginally slower than that of the parent strain. The Δald1 Δald2 double-disruption strain failed to grow on glucose alone, but growth was restored by the addition of acetate, indicating that both ALDHs might catalyze the oxidation of acetaldehyde produced during fermentation. The double-disruption strain grew very slowly on ethanol. The role of mitochondrial ALDH5 in acetaldehyde metabolism has not been defined but appears to be unimportant.
PMCID: PMC106960  PMID: 9473035
8.  Aldehyde dehydrogenase 1B1 (ALDH1B1) Is a Potential Biomarker for Human Colon Cancer 
Aldehyde dehydrogenases (ALDHs) belong to a superfamily of NAD(P)+-dependent enzymes, which catalyze the oxidation of endogenous and exogenous aldehydes to their corresponding acids. Increased expression and/or activity of ALDHs, particularly ALDH1A1, have been reported to occur in human cancers. It is proposed that the metabolic function of ALDH1A1 confers the “stemness” properties to normal and cancer stem cells. Nevertheless, the identity of ALDH isozymes that contribute to the enhanced ALDH activity in specific types of human cancers remains to be elucidated. ALDH1B1 is a mitochondrial ALDH that metabolizes a wide range of aldehyde substrates including acetaldehyde and products of lipid peroxidation (LPO). In the present study, we immunohistochemically examined the expression profile of ALDH1A1 and ALDH1B1 in human adenocarcinomas of colon (N=40), lung (N=30), breast (N=33) and ovary (N=33) using an NIH tissue array. The immunohistochemical expression of ALDH1A1 or ALDH1B1 in tumor tissues was scored by their intensity (scale = 1–3) and extensiveness (% of total cancer cells). Herein we report a 5.6-fold higher expression score for ALDH1B1 in cancerous tissues than that for ALDH1A1. Remarkably, 39 out of 40 colonic cancer specimens were positive for ALDH1B1 with a staining intensity of 2.8 ± 0.5. Our study demonstrates that ALDH1B1 is more profoundly expressed in the adenocarcinomas examined in this study relative to ALDH1A1 and that ALDH1B1 is dramatically upregulated in human colonic adenocarcinoma, making it a potential biomarker for human colon cancer.
doi:10.1016/j.bbrc.2011.01.002
PMCID: PMC3112362  PMID: 21216231
ALDH1B1; epithelial cancer; colon cancer; cancer stem cell; biomarker
9.  Post-translational modifications of mitochondrial aldehyde dehydrogenase and biomedical implications 
Journal of proteomics  2011;74(12):2691-2702.
Aldehyde dehydrogenases (ALDHs) represent large family members of NAD(P)+-dependent dehydrogenases responsible for the irreversible metabolism of many endogenous and exogenous aldehydes to the corresponding acids. Among 19 ALDH isozymes, mitochondrial ALDH2 is a low Km enzyme responsible for the metabolism of acetaldehyde and lipid peroxides such as malondialdehyde and 4-hydroxynonenal, both of which are highly reactive and toxic. Consequently, inhibition of ALDH2 would lead to elevated levels of acetaldehyde and other reactive lipid peroxides following ethanol intake and/or exposure to toxic chemicals. In addition, many East Asian people with a dominant negative mutation in ALDH2 gene possess a decreased ALDH2 activity with increased risks for various types of cancer, myocardial infarct, alcoholic liver disease, and other pathological conditions. The aim of this review is to briefly describe the multiple post-translational modifications of mitochondrial ALDH2, as an example, after exposure to toxic chemicals or under different disease states and their pathophysiological roles in promoting alcohol/drug-mediated tissue damage. We also briefly mention exciting preclinical translational research opportunities to identify small molecule activators of ALDH2 and its isozymes as potentially therapeutic/preventive agents against various disease states where the expression or activity of ALDH enzymes is altered or inactivated.
doi:10.1016/j.jprot.2011.05.013
PMCID: PMC3177986  PMID: 21609791
Aldehyde dehydrogenases; post-translational modifications; cellular defense; drug toxicity; disease states; translational research
10.  ALDH2 Activator Inhibits Increased Myocardial Infarction Injury by Nitroglycerin Tolerance 
Science translational medicine  2011;3(107):107ra111.
Nitroglycerin, which helps impaired cardiac function as it is converted to nitric oxide, is used worldwide to treat patients with various ischemic and congestive cardiac diseases, including angina pectoris. Nevertheless, after continuous treatment, the benefits of nitroglycerin are limited by the development of tolerance to the drug. Nitroglycerin tolerance is a result of inactivation of aldehyde dehydrogenase 2 (ALDH2), an enzyme essential for cardioprotection in animals subjected to myocardial infarction (MI). Here we tested the hypothesis that the tolerance that develops as a result of sustained nitroglycerin treatment increases cardiac injury by subsequent MI. In a rat model of MI, 16 hours of prior, sustained nitroglycerin treatment (7.2 mg/kg/day) resulted in infarcts that were twice as large as those in untreated control animals and in diminished cardiac function at 3 days and 2 weeks after the MI. We also sought to identify a potential treatment to protect against this increased cardiac damage. Nitroglycerin inhibited ALDH2 activity in vitro, an effect that was blocked by Alda-1, an activator of ALDH2. Co-administration of Alda-1 (16 mg/kg/day) with the nitroglycerin prevented the nitroglycerin-induced increase in cardiac dysfunction after MI in rats, at least in part by enhancing metabolism of reactive aldehyde adducts that impair normal protein functions. If our animal studies showing that nitroglycerin tolerance increases cardiac injury upon ischemic insult are corroborated in humans, activators of ALDH2 such as Alda-1 may help to protect MI patients from this nitroglycerin-induced increase in cardiac injury, while maintaining the cardiac benefits of the increased nitric oxide concentrations produced by nitroglycerin.
doi:10.1126/scitranslmed.3002067
PMCID: PMC3547591  PMID: 22049071
11.  AMP-Dependent Kinase and Autophagic Flux are Involved in Aldehyde Dehydrogenase 2-Offered Protection against Cardiac Toxicity of Ethanol 
Free radical biology & medicine  2011;51(9):1736-1748.
Mitochondrial aldehyde dehydrogenase-2 (ALDH2) alleviates ethanol toxicity although the precise mechanism is unclear. This study was designed to evaluate the effect of ALDH2 on ethanol-induced myocardial damage with a focus on autophagy. Wild-type FVB and transgenic mice overexpressing ALDH2 were challenged with ethanol (3 g/kg/d, i.p.) for 3 days and cardiac mechanical function was assessed using the echocardiographic and IonOptix systems. Western blot analysis was used to evaluate essential autophagy markers, Akt and AMPK and their downstream signaling mTOR. Ethanol challenge altered cardiac geometry and function evidenced by enlarged ventricular end systolic and diastolic diameters, decreased cell shortening and intracellular Ca2+ rise, prolonged relengthening and intracellular Ca2+ decay, as well as reduced SERCA Ca2+ uptake, the effects of which were mitigated by ALDH2. Ethanol challenge facilitated myocardial autophagy as evidenced by enhanced expression of Beclin, ATG7 and LC3B II, as well as mTOR dephosphorylation, which was alleviated by ALDH2. Ethanol challenge-induced cardiac defect and apoptosis were reversed by the ALDH-2 agonist Alda-1, the autophagy inhibitor 3-MA, and the AMPK inhibitor compound C whereas the autophagy inducer rapamycin and the AMPK activator AICAR mimicked or exacerbated ethanol-induced cell injury. Ethanol promoted or suppressed phosphorylation of AMPK and Akt, respectively, in FVB but not ALDH2 murine hearts. Moreover, AICAR nullified Alda-1-induced protection against ethanol-triggered autophagic and functional changes. Ethanol increased GFP-LC3 puncta in H9c2 cells, the effect of which was ablated by Alda-1 and 3-MA. Lysosomal inhibition using bafilomycin A1, E64D and pepstatin A obliterated Alda-1- but not ethanol-induced responses in GFP-LC3 puncta. Our results suggested that ALDH2 protects against ethanol toxicity through altered Akt and AMPK signaling and regulation of autophagic flux.
doi:10.1016/j.freeradbiomed.2011.08.002
PMCID: PMC3188331  PMID: 21871561
Ethanol; ALDH2; myocardial dysfunction; autophagy; autophagy flux; Akt; AMPK
12.  The mutation in the mitochondrial aldehyde dehydrogenase (ALDH2) gene responsible for alcohol-induced flushing increases turnover of the enzyme tetramers in a dominant fashion. 
Journal of Clinical Investigation  1996;98(9):2027-2032.
Deficiency in mitochondrial aldehyde dehydrogenase (ALDH2), a tetrameric enzyme, results from inheriting one or two ALDH2*2 alleles. This allele encodes a protein subunit with a lysine for glutamate substitution at position 487 and is dominant over the wild-type allele, ALDH2*1. The ALDH2*2-encoded subunit (ALDH2K) reduces the activity of ALDH2 enzyme in cell lines expressing the wild-type subunit (ALDH2E). In addition to this effect on the enzyme activity, we now report that ALDH2*2 heterozygotes had lower levels of ALDH2 immunoreactive protein in autopsy liver samples. The half-lives of ALDH2 protein in HeLa cell lines expressing ALDH2*1, ALDH2*2, or both were determined by the rate of loss of immunoreactive protein after inhibition of protein synthesis with puromycin and by pulse-chase experiments. By either measure, ALDH2E enzyme was very stable, with a half-life of at least 22 h. ALDH2K enzyme had an enzyme half-life of only 14 h. In cells expressing both subunits, most of the subunits assemble as heterotetramers, and these enzymes had a half-life of 13 h. Thus, the effect of ALDH2K on enzyme turnover is dominant. These studies indicate that the ALDH2*2 allele exerts its dominant effect both by interfering with the catalytic activity of the enzyme and by increasing its turnover. This represents the first example of a dominantly acting allele with this effect on a mitochondrial enzyme's turnover.
PMCID: PMC507646  PMID: 8903321
13.  Refined Geographic Distribution of the Oriental ALDH2*504Lys (nee 487Lys) Variant 
Annals of human genetics  2009;73(Pt 3):335-345.
Summary
Mitochondrial aldehyde dehydrogenase (ALDH2) is one of the most important enzymes in human alcohol metabolism. The oriental ALDH2*504Lys variant functions as a dominant negative greatly reducing activity in heterozygotes and abolishing activity in homozygotes. This allele is associated with serious disorders such as alcohol liver disease, late onset Alzheimer disease, colorectal cancer, and esophageal cancer, and is best known for protection against alcoholism. Many hundreds of papers in various languages have been published on this variant, providing allele frequency data for many different populations. To develop a highly refined global geographic distribution of ALDH2*504Lys, we have collected new data on 4,091 individuals from 86 population samples and assembled published data on a total of 80,691 individuals from 366 population samples. The allele is essentially absent in all parts of the world except East Asia. The ALDH2*504Lys allele has its highest frequency in Southeast China, and occurs in most areas of China, Japan, Korea, Mongolia, and Indochina with frequencies gradually declining radially from Southeast China. As the indigenous populations in South China have much lower frequencies than the southern Han migrants from Central China, we conclude that ALDH2*504Lys was carried by Han Chinese as they spread throughout East Asia. Esophageal cancer, with its highest incidence in East Asia, may be associated with ALDH2*504Lys because of a toxic effect of increased acetaldehyde in the tissue where ingested ethanol has its highest concentration. While the distributions of esophageal cancer and ALDH2*504Lys do not precisely correlate, that does not disprove the hypothesis. In general the study of fine scale geographic distributions of ALDH2*504Lys and diseases may help in understanding the multiple relationships among genes, diseases, environments, and cultures.
doi:10.1111/j.1469-1809.2009.00517.x
PMCID: PMC2846302  PMID: 19456322
East Asia; aldehyde dehydrogenase 2; alcohol associated; allele frequency; esophageal cancer
14.  Impaired Cardiac SIRT1 Activity by Carbonyl Stress Contributes to Aging-Related Ischemic Intolerance 
PLoS ONE  2013;8(9):e74050.
Reactive aldehydes can initiate protein oxidative damage which may contribute to heart senescence. Sirtuin 1 (SIRT1) is considered to be a potential interventional target for I/R injury management in the elderly. We hypothesized that aldehyde mediated carbonyl stress increases susceptibility of aged hearts to ischemia/reperfusion (I/R) injury, and elucidate the underlying mechanisms with a focus on SIRT1. Male C57BL/6 young (4-6 mo) and aged (22-24 mo) mice were subjected to myocardial I/R. Cardiac aldehyde dehydrogenase (ALDH2), SIRT1 activity and protein carbonyls were assessed. Our data revealed that aged heart exhibited increased endogenous aldehyde/carbonyl stress due to impaired ALDH2 activity concomitant with blunted SIRT1 activity (P<0.05). Exogenous toxic aldehydes (4-HNE) exposure in isolated cardiomyocyte verified that aldehyde-induced carbonyl modification on SIRT1 impaired SIRT1 activity leading to worse hypoxia/reoxygenation (H/R) injury, which could all be rescued by Alda-1 (ALDH2 activator) (all P<0.05). However, SIRT1 inhibitor blocked the protective effect of Alda-1 on H/R cardiomyocyte. Interestingly, myocardial I/R leads to higher carbonylation but lower activity of SIRT1 in aged hearts than that seen in young hearts (P<0.05). The application of Alda-1 significantly reduced the carbonylation on SIRT1 and markedly improved the tolerance to in vivo I/R injury in aged hearts, but failed to protect Sirt1+/− knockout mice against myocardial I/R injury. This was verified by Alda-1 treatment improved postischemic contractile function recovery in ex vivo perfused aged but not in Sirt1+/− hearts. Thus, aldehyde/carbonyl stress is accelerated in aging heart. These results provide a new insight that impaired cardiac SIRT1 activity by carbonyl stress plays a critical role in the increased susceptibility of aged heart to I/R injury. ALDH2 activation can restore this aging-related myocardial ischemic intolerance.
doi:10.1371/journal.pone.0074050
PMCID: PMC3769351  PMID: 24040162
15.  Bioactivation of Nitroglycerin by Purified Mitochondrial and Cytosolic Aldehyde Dehydrogenases* 
The Journal of Biological Chemistry  2008;283(26):17873-17880.
Metabolism of nitroglycerin (GTN) to 1,2-glycerol dinitrate (GDN) and nitrite by mitochondrial aldehyde dehydrogenase (ALDH2) is essentially involved in GTN bioactivation resulting in cyclic GMP-mediated vascular relaxation. The link between nitrite formation and activation of soluble guanylate cyclase (sGC) is still unclear. To test the hypothesis that the ALDH2 reaction is sufficient for GTN bioactivation, we measured GTN-induced formation of cGMP by purified sGC in the presence of purified ALDH2 and used a Clark-type electrode to probe for nitric oxide (NO) formation. In addition, we studied whether GTN bioactivation is a specific feature of ALDH2 or is also catalyzed by the cytosolic isoform (ALDH1). Purified ALDH1 and ALDH2 metabolized GTN to 1,2- and 1,3-GDN with predominant formation of the 1,2-isomer that was inhibited by chloral hydrate (ALDH1 and ALDH2) and daidzin (ALDH2). GTN had no effect on sGC activity in the presence of bovine serum albumin but caused pronounced cGMP accumulation in the presence of ALDH1 or ALDH2. The effects of the ALDH isoforms were dependent on the amount of added protein and, like 1,2-GDN formation, were sensitive to ALDH inhibitors. GTN caused biphasic sGC activation with apparent EC50 values of 42 ± 2.9 and 3.1 ± 0.4 μm in the presence of ALDH1 and ALDH2, respectively. Incubation of ALDH1 or ALDH2 with GTN resulted in sustained, chloral hydrate-sensitive formation of NO. These data may explain the coupling of ALDH2-catalyzed GTN metabolism to sGC activation in vascular smooth muscle.
doi:10.1074/jbc.M801182200
PMCID: PMC2440601  PMID: 18450747
16.  Comparative genomics, molecular evolution and computational modeling of ALDH1B1 and ALDH2 
Chemico-biological interactions  2012;202(0):11-21.
Vertebrate ALDH2 genes encode mitochondrial enzymes capable of metabolizing acetaldehyde and other biological aldehydes in the body. Mammalian ALDH1B1, another mitochondrial enzyme sharing 72% identity with ALDH2, is also capable of metabolizing acetaldehyde but has a tissue distribution and pattern of activity distinct from that of ALDH2. Bioinformatic analyses of several vertebrate genomes were undertaken using known ALDH2 and ALDH1B1 amino acid sequences. Phylogenetic analysis of many representative vertebrate species (including fish, amphibians, birds and mammals) indicated the presence of ALDH1B1 in many mammalian species and in frogs (Xenopus tropicalis); no evidence was found for ALDH1B1 in the genomes of birds, reptiles or fish. Predicted vertebrate ALDH2 and ALDH1B1 subunit sequences and structures were highly conserved, including residues previously shown to be involved in catalysis and coenzyme binding for human ALDH2. Studies of ALDH1B1 sequences supported the hypothesis that the ALDH1B1 gene originated in early vertebrates from a retrotransposition of the vertebrate ALDH2 gene. Given the high degree of similarity between ALDH2 and ALDH1B1, it is surprising that individuals with an inactivating mutation in ALDH2 (ALDH2*2) do not exhibit a compensatory increase in ALDH1B1 activity. We hypothesized that the similarity between the two ALDHs would allow for dominant negative heterotetramerization between the inactive ALDH2 mutants and ALDH1B1. Computational-based molecular modeling studies examining predicted protein-protein interactions indicated that heterotetramerization between ALDH2 and ALDH1B1 subunits was highly probable and may partially explain a lack of compensation by ALDH1B1 in ALDH2*2 individuals.
doi:10.1016/j.cbi.2012.11.022
PMCID: PMC3687035  PMID: 23247008
Aldehyde dehydrogenases; ALDH1B1; ALDH2; ALDH2*2; Heterotetramerization; Retrotransposition
17.  Multiple and Additive Functions of ALDH3A1 and ALDH1A1: CATARACT PHENOTYPE AND OCULAR OXIDATIVE DAMAGE IN Aldh3a1(−/−)/Aldh1a1(−/−) KNOCK-OUT MICE*S 
The Journal of biological chemistry  2007;282(35):25668-25676.
ALDH3A1 (aldehyde dehydrogenase 3A1) is abundant in the mouse cornea but undetectable in the lens, and ALDH1A1 is present at lower (catalytic) levels in the cornea and lens. To test the hypothesis that ALDH3A1 and ALDH1A1 protect the anterior segment of the eye against environmentally induced oxidative damage, Aldh1a1(−/−)/Aldh3a1(−/−) double knock-out and Aldh1a1(−/−) and Aldh3a1(−/−) single knock-out mice were evaluated for biochemical changes and cataract formation (lens opacification). The Aldh1a1/Aldh3a1- and Aldh3a1-null mice develop cataracts in the anterior and posterior subcapsular regions as well as punctate opacities in the cortex by 1 month of age. The Aldh1a1-null mice also develop cataracts later in life (6–9 months of age). One- to three-month-old Aldh-null mice exposed to UVB exhibited accelerated anterior lens subcapsular opacification, which was more pronounced in Aldh3a1(−/−) and Aldh3a1(−/−)/Aldh1a1(−/−) mice compared with Aldh1a1(−/−) and wild type animals. Cataract formation was associated with decreased proteasomal activity, increased protein oxidation, increased GSH levels, and increased levels of 4-hydroxy-2-nonenal- and malondialdehyde-protein adducts. In conclusion, these findings support the hypothesis that corneal ALDH3A1 and lens ALDH1A1 protect the eye against cataract formation via nonenzymatic (light filtering) and enzymatic (detoxification) functions.
doi:10.1074/jbc.M702076200
PMCID: PMC2253645  PMID: 17567582
18.  Developmental Trajectory and Environmental Moderation of the Effect of ALDH2 Polymorphism on Alcohol Use 
Background
In the aldehyde dehydrogenase 2 (ALDH2) gene, the ALDH2*2 allele, prevalent in East Asian populations, encodes an enzyme with severely reduced activity, thereby disrupting the normal metabolism of alcohol. Possession of the ALDH2*2 allele has been repeatedly shown to be associated with lower risk for alcohol dependence, and reduced alcohol use. However, relatively few studies have considered whether the magnitude of the effect of ALDH2 polymorphism upon drinking is related to developmental stage, or varies by environmental context.
Methods
In a longitudinally assessed sample of 356 adopted adolescents and young adults of East Asian descent, we examined the progression over time of the relationship between ALDH2 genotype and multiple measures of drinking behavior. We also sought to determine whether the environmental influences of non-biological parent and elder sibling alcohol use and misuse, as well as deviant peer behavior, moderated the effect of ALDH2 genotype upon alcohol use.
Results
Across all measures of alcohol use, the association between ALDH2*2 allele possession and reduced drinking went from negligible to moderate between mid-adolescence and early adulthood. A combined index of adoptive parent alcohol use and misuse consistently moderated the protective effect of the ALDH2*2 allele across measures of quantity and frequency of alcohol use, and symptomology, such that high parental alcohol use and misuse reduced the protective effect of the ALDH2*2 allele, while low parental alcohol use and misuse enhanced the effect of the allele. Neither a combined index of elder sibling alcohol use and misuse, nor deviant peer behavior were consistently related to the effect of ALDH2 genotype.
Conclusions
The protective effect of the ALDH2*2 allele increases over the course of adolescence and young adulthood and is modified by the environmental influence of parental alcohol use and misuse. As such, ALDH2 provides a model system for exploring the nature of gene-environment interplay across development.
doi:10.1111/j.1530-0277.2012.01809.x
PMCID: PMC3416945  PMID: 22563891
Gene-environment Interplay; Aldehyde Dehydrogenase; ALDH2; Adoption; Asian-Americans
19.  Expression of the Vibrio cholerae gene encoding aldehyde dehydrogenase is under control of ToxR, the cholera toxin transcriptional activator. 
Journal of Bacteriology  1991;173(9):2842-2851.
The toxR gene of Vibrio cholerae encodes a transcriptional activator required for the expression of the cholera toxin genes (ctxAB) and more than 15 other genes encoding secreted or membrane proteins. The latter group includes virulence genes involved in the biogenesis of the TCP pilus, the accessory colonization factor, and such ToxR-activated genes as tagA, mutations in which cause no detectable virulence defect in the suckling mouse model. To analyze the regulation of expression and the structure of tagA, we have cloned and sequenced about 2 kb of DNA upstream from a tagA::TnphoA fusion. While the portion of the tagA gene product examined presented no extensive similarity to any known protein, the amino acid sequence deduced from an open reading frame (designated aldA) located upstream from and in opposite orientation to tagA was highly similar to the sequences of eukaryotic aldehyde dehydrogenases. An assay of aldehyde dehydrogenase activity in extracts of a wild-type V. cholerae strainand an aldA mutant confirmed that aldA encodes an aldehyde dehydrogenase. Expression of the aldA gene was studied together with that of tagA in both V. cholerae and Escherichia coli. The expression of both tagA and aldA was environmentally regulated and dependent on a functional toxR gene in V. cholerae, but neither promoter was activated by ToxR in E. coli, suggesting that expression of tagA and aldA requires an additional transcriptional activator besides ToxR. The aldA gene is the first example of a gene encoding a cytoplasmic protein that is under the control of ToxR, and this suggests that metabolic enzymes may constitute novel members of virulence regulons in bacteria.
Images
PMCID: PMC207865  PMID: 1902210
20.  The roles of aldehyde dehydrogenases (ALDHs) in the PDH bypass of Arabidopsis 
BMC Biochemistry  2009;10:7.
Background
Eukaryotic aldehyde dehydrogenases (ALDHs, EC 1.2.1), which oxidize aldehydes into carboxylic acids, have been classified into more than 20 families. In mammals, Family 2 ALDHs detoxify acetaldehyde. It has been hypothesized that plant Family 2 ALDHs oxidize acetaldehyde generated via ethanolic fermentation, producing acetate for acetyl-CoA biosynthesis via acetyl-CoA synthetase (ACS), similar to the yeast pathway termed the "pyruvate dehydrogenase (PDH) bypass". Evidence for this pathway in plants has been obtained from pollen.
Results
To test for the presence of the PDH bypass in the sporophytic tissue of plants, Arabidopsis plants homozygous for mutant alleles of all three Family 2 ALDH genes were fed with 14C-ethanol along with wild type controls. Comparisons of the incorporation rates of 14C-ethanol into fatty acids in mutants and wild type controls provided direct evidence for the presence of the PDH bypass in sporophytic tissue. Among the three Family 2 ALDHs, one of the two mitochondrial ALDHs (ALDH2B4) appears to be the primary contributor to this pathway. Surprisingly, single, double and triple ALDH mutants of Arabidopsis did not exhibit detectable phenotypes, even though a Family 2 ALDH gene is required for normal anther development in maize.
Conclusion
The PDH bypass is active in sporophytic tissue of plants. Blocking this pathway via triple ALDH mutants does not uncover obvious visible phenotypes.
doi:10.1186/1471-2091-10-7
PMCID: PMC2670319  PMID: 19320993
21.  Aldehyde Dehydrogenase 2 Knockout Accentuates Ethanol-Induced Cardiac Depression: Role of Protein Phosphatases 
Alcohol consumption leads to myocardial contractile dysfunction possibly due to the toxicity of ethanol and its major metabolite acetaldehyde. This study was designed to examine the influence of mitochondrial aldehyde dehydrogenase-2 (ALDH2) knockout (KO) on acute ethanol exposure-induced cardiomyocyte dysfunction. Wild-type (WT) and ALDH2 KO mice were subjected to acute ethanol (3 g/kg, i.p.) challenge and cardiomyocyte contractile function was assessed 24 hrs later using an IonOptix® edge-detection system. Western blot analysis was performed to evaluate ALDH2, protein phosphatase 2A (PP2A), phosphorylation of Akt and glycogen synthase kinase-3β (GSK-3β). ALDH2 KO accentuated ethanol-induced elevation in cardiac acetaldehyde levels. Ethanol exposure depressed cardiomyocyte contractile function including decreased cell shortening amplitude and maximal velocity of shortening/relengthening as well as prolonged relengthening duration and a greater decline in peak shortening in response to increasing stimulus frequency, the effect of which was significantly exaggerated by ALDH2 KO. ALDH2 KO also unmasked an ethanol-induced prolongation of shortening duration. In addition, short-term in vitro incubation of ethanol-induced cardiomyocyte mechanical defects were exacerbated by the ALDH inhibitor cyanamide. Ethanol treatment dampened phosphorylation of Akt and GSK-3β associated with up-regulated PP2A, which was accentuated by ALDH2 KO. ALDH2 KO aggravated ethanol-induced decrease in mitochondrial membrane potential. These results suggested that ALDH2 deficiency led to worsened ethanol-induced cardiomyocyte function, possibly due to upregulated expression of protein phosphatase, depressed Akt activation and subsequently impaired mitochondrial function. These findings depict a critical role of ALDH2 in the pathogenesis of alcoholic cardiomyopathy.
doi:10.1016/j.yjmcc.2010.03.017
PMCID: PMC2885537  PMID: 20362583
Ethanol; ALDH2; Cardiomyocyte; Contractile function; Akt; Protein phosphatase
22.  Aldehyde dehydrogenase 7A1 (ALDH7A1) attenuates reactive aldehyde and oxidative stress induced cytotoxicity 
Chemico-Biological Interactions  2011;191(1-3):269-277.
Mammalian aldehyde dehydrogenase 7A1 (ALDH7A1) is homologous to plant ALDH7B1 which protects against various forms of stress such as increased salinity, dehydration and treatment with oxidants or pesticides. Deleterious mutations in human ALDH7A1 are responsible for pyridoxine-dependent and folinic acid-responsive seizures. In previous studies, we have shown that human ALDH7A1 protects against hyperosmotic stress presumably through the generation of betaine, an important cellular osmolyte, formed from betaine aldehyde. Hyperosmotic stress is coupled to an increase in oxidative stress and lipid peroxidation (LPO). In this study, cell viability assays revealed that stable expression of mitochondrial ALDH7A1 in Chinese hamster ovary (CHO) cells provides significant protection against treatment with the LPO-derived aldehydes hexanal and 4-hydroxy-2-nonenal (4HNE) implicating a protective function for the enzyme during oxidative stress. A significant increase in cell survival was also observed in CHO cells expressing either mitochondrial or cytosolic ALDH7A1 treated with increasing concentrations of hydrogen peroxide (H2O2) or 4HNE, providing further evidence for anti-oxidant activity. In vitro enzyme activity assays indicate that human ALDH7A1 is sensitive to oxidation and that efficiency can be at least partially restored by incubating recombinant protein with the thiol reducing agent β-mercaptoethanol (BME). We also show that after reactivation with BME, recombinant ALDH7A1 is capable of metabolizing the reactive aldehyde 4HNE. In conclusion, ALDH7A1 mechanistically appears to provide cells protection through multiple pathways including the removal of toxic LPO-derived aldehydes in addition to osmolyte generation.
doi:10.1016/j.cbi.2011.02.016
PMCID: PMC3387551  PMID: 21338592
Aldehyde dehydrogenase 7A1; ALDH7A1; Antiquitin; Oxidative stress; 4HNE; 4-Hydroxynonenal
23.  Differential Metabolism of Organic Nitrates by Aldehyde Dehydrogenase 1a1 and 2: Substrate Selectivity, Enzyme Inactivation, and Active Cysteine Sites 
The AAPS Journal  2011;13(4):548-555.
Organic nitrate vasodilators (ORN) exert their pharmacologic effects through the metabolic release of nitric oxide (NO). Mitochondrial aldehyde dehydrogenase (ALDH2) is the principal enzyme responsible for NO liberation from nitroglycerin (NTG), but lacks activity towards other ORN. Cytosolic aldehyde dehydrogenase (ALDH1a1) can produce NO from NTG, but its activity towards other ORN is unknown. Using purified enzymes, we showed that both isoforms could liberate NO from NTG, isosorbide dinitrate (ISDN), and nicrorandil, while only ALDH1a1 metabolized isosorbide-2-mononitrate and isosorbide-5-mononitrate (IS-5-MN). Following a 10-min incubation with purified enzyme, 0.1 mM NTG and 1 mM ISDN potently inactivated ALDH1a1 (to 21.9% ± 11.1% and 0.44% ± 1.04% of control activity, respectively) and ALDH2 (no activity remaining and 4.57% ± 7.92% of control activity, respectively), while 1 mM IS-5-MN exerted only modest inactivation of ALDH1a1 (reduced to 89% ± 4.3% of control). Cytosolic ALDH in hepatic homogenates incubated at the vascular EC50 concentrations of ORN was inactivated by NTG (to 45.1% ± 8.1% of control activity) while mitochondrial ALDH was inactivated by NTG and nicorandil (to 68.2% ± 10.0% and 78.7% ± 19.8% of control, respectively). Via site-directed mutagenesis, the active sites of ORN metabolism of ALDH2 (Cys-319) and ALDH1a1 (Cys-303) were found to be identical to those responsible for their dehydrogenase activity. Cysteine-302 of ALDH1a1 and glutamate-504 of ALDH2 were found to modulate the rate of ORN metabolism. These studies provide further characterization of the substrate selectivity, inactivation, and active sites of ALDH2 and ALDH1a1 toward ORN.
doi:10.1208/s12248-011-9295-4
PMCID: PMC3231853  PMID: 21818694
aldehyde dehydrogenase; nitric oxide; organic nitrate; site-directed mutagenesis
24.  Characterization of aldehyde dehydrogenase isozymes in ovarian cancer tissues and sphere cultures 
BMC Cancer  2012;12:329.
Background
Aldehyde dehydrogenases belong to a superfamily of detoxifying enzymes that protect cells from carcinogenic aldehydes. Of the superfamily, ALDH1A1 has gained most attention because current studies have shown that its expression is associated with human cancer stem cells. However, ALDH1A1 is only one of the 19 human ALDH subfamilies currently known. The purpose of the present study was to determine if the expression and activities of other major ALDH isozymes are associated with human ovarian cancer and ovarian cancer sphere cultures.
Methods
Immunohistochemistry was used to delineate ALDH isozyme localization in clinical ovarian tissues. Western Blot analyses were performed on lysates prepared from cancer cell lines and ovarian cancer spheres to confirm the immunohistochemistry findings. Quantitative reverse transcription-polymerase chain reactions were used to measure the mRNA expression levels. The Aldefluor® assay was used to measure ALDH activity in cancer cells from the four tumor subtypes.
Results
Immunohistochemical staining showed significant overexpression of ALDH1A3, ALDH3A2, and ALDH7A1 isozymes in ovarian tumors relative to normal ovarian tissues. The expression and activity of ALDH1A1 is tumor type-dependent, as seen from immunohistochemisty, Western blot analysis, and the Aldefluor® assay. The expression was elevated in the mucinous and endometrioid ovarian epithelial tumors than in serous and clear cell tumors. In some serous and most clear cell tumors, ALDH1A1 expression was found in the stromal fibroblasts. RNA expression of all studied ALDH isozymes also showed higher expression in endometrioid and mucinous tumors than in the serous and clear cell subtypes. The expression of ALDH enzymes showed tumor type-dependent induction in ovarian cancer cells growing as sphere suspensions in serum-free medium.
Conclusions
The results of our study indicate that ALDH enzyme expression and activity may be associated with specific cell types in ovarian tumor tissues and vary according to cell states. Elucidating the function of the ALDH isozymes in lineage differentiation and pathogenesis may have significant implications for ovarian cancer pathophysiology.
doi:10.1186/1471-2407-12-329
PMCID: PMC3458927  PMID: 22852552
Aldehyde dehydrogenase; Isozymes; Ovarian tumors; Sphere cultures; Tumor-type specific expression
25.  Selective ALDH3A1 Inhibition by Benzimidazole Analogues Increase Mafosfamide Sensitivity in Cancer Cells 
Journal of Medicinal Chemistry  2014;57(2):449-461.
Aldehyde dehydrogenase enzymes irreversibly oxidize aldehydes generated from metabolism of amino acids, fatty acids, food, smoke, additives, and xenobiotic drugs. Cyclophosphamide is one such xenobiotic used in cancer therapies. Upon activation, cyclophosphamide forms an intermediate, aldophosphamide, which can be detoxified to carboxyphosphamide by aldehyde dehydrogenases (ALDH), especially ALDH1A1 and ALDH3A1. Consequently, selective inhibition of ALDH3A1 could increase chemosensitivity toward cyclophosphamide in ALDH3A1 expressing tumors. Here, we report detailed kinetics and structural characterization of a highly selective submicromolar inhibitor of ALDH3A1, 1-[(4-fluorophenyl)sulfonyl]-2-methyl-1H-benzimidazole (CB7, IC50 of 0.2 μM). CB7 does not inhibit ALDH1A1, ALDH1A2, ALDH1A3, ALDH1B1, or ALDH2 activity. Structural, kinetics, and mutagenesis studies show that CB7 binds to the aldehyde binding pocket of ALDH3A1. ALDH3A1-expressing lung adenocarcinoma and glioblastoma cell lines are sensitized toward mafosfamide (MF) treatment in the presence analogues of CB7, whereas primary lung fibroblasts lacking ALDH3A1 expression, are not.
doi:10.1021/jm401508p
PMCID: PMC3988914  PMID: 24387105

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