Pharmacological chaperone therapies: Can aldehyde dehydrogenase activator make us healthier?
Authors: Laurent Dollé, Bin Gao
Journal: Journal of Hepatology (2015)

Pharmacological activation of aldehyde dehydrogenase 2 by Alda-1 reverses alcohol-induced hepatic steatosis and cell death in miceJournal of HepatologyVol. 62Issue 6PreviewAlcoholic liver disease (ALD) is a major cause of morbidity and mortality worldwide [1]. Although great efforts to explore potential therapeutic targets for ALD have been made for decades, effective therapies for any stage of ALD are currently lacking. Full-Text PDF Alcoholic liver disease (ALD) is characterized by the development of steatosis, inflammation, hepatocyte necrosis, and apoptosis, with eventual development of fibrosis and cirrhosis [1Gao B. Bataller R. Alcoholic liver disease: pathogenesis and new therapeutic targets.Gastroenterology. 2011; 141: 1572-1585Abstract Full Text Full Text PDF PubMed Scopus (1446) Google Scholar, 2Tilg H. Moschen A.R. Kaneider N.C. Pathways of liver injury in alcoholic liver disease.J Hepatol. 2011; 55: 1159-1161Abstract Full Text Full Text PDF PubMed Scopus (80) Google Scholar, 3Rusyn I. Bataller R. Alcohol and toxicity.J Hepatol. 2013; 59: 387-388Abstract Full Text Full Text PDF PubMed Scopus (56) Google Scholar]. Despite being one of the major causes of morbidity and mortality in the world, there are actually no current effective drug treatments for severe ALD [1Gao B. Bataller R. Alcoholic liver disease: pathogenesis and new therapeutic targets.Gastroenterology. 2011; 141: 1572-1585Abstract Full Text Full Text PDF PubMed Scopus (1446) Google Scholar, 2Tilg H. Moschen A.R. Kaneider N.C. Pathways of liver injury in alcoholic liver disease.J Hepatol. 2011; 55: 1159-1161Abstract Full Text Full Text PDF PubMed Scopus (80) Google Scholar, 3Rusyn I. Bataller R. Alcohol and toxicity.J Hepatol. 2013; 59: 387-388Abstract Full Text Full Text PDF PubMed Scopus (56) Google Scholar]. Accumulating evidence suggests that ethanol metabolite acetaldehyde and its by-products (such as: 4-hydroxy-2-nonenal (4-HNE), and malondialdehyde (MDA)) are highly toxic and even carcinogenic, contributing to the pathogenesis of various alcohol-associated disorders including ALD [1Gao B. Bataller R. Alcoholic liver disease: pathogenesis and new therapeutic targets.Gastroenterology. 2011; 141: 1572-1585Abstract Full Text Full Text PDF PubMed Scopus (1446) Google Scholar, 2Tilg H. Moschen A.R. Kaneider N.C. Pathways of liver injury in alcoholic liver disease.J Hepatol. 2011; 55: 1159-1161Abstract Full Text Full Text PDF PubMed Scopus (80) Google Scholar, 3Rusyn I. Bataller R. Alcohol and toxicity.J Hepatol. 2013; 59: 387-388Abstract Full Text Full Text PDF PubMed Scopus (56) Google Scholar]. Over the last twenty years, researchers have been extensively exploring drugs that can activate aldehyde dehydrogenase (ALDH) enzyme and subsequently accelerate acetaldehyde clearance [[4]Chen C.H. Ferreira J.C. Gross E.R. Mochly-Rosen D. Targeting aldehyde dehydrogenase 2: new therapeutic opportunities.Physiol Rev. 2014; 94: 1-34Crossref PubMed Scopus (414) Google Scholar], and have demonstrated that these ALDH activators (e.g. ALDH activator-1: Alda-1) can protect against ethanol-induced cardiac injury, ischemic brain injury, radiation dermatitis etc. in animal models [[4]Chen C.H. Ferreira J.C. Gross E.R. Mochly-Rosen D. Targeting aldehyde dehydrogenase 2: new therapeutic opportunities.Physiol Rev. 2014; 94: 1-34Crossref PubMed Scopus (414) Google Scholar]. In this issue of the Journal of Hepatology, Zhong et al. [[5]Zhong W. Zhang W. Li Q. Xie G. Sun Q. Sun X. et al.Pharmacological activation of aldehyde dehydrogenase 2 by Alda-1 reverses alcohol-induced hepatic steatosis and cell death in mice.J Hepatol. 2015; 62: 1375-1381Abstract Full Text Full Text PDF PubMed Scopus (77) Google Scholar] nicely demonstrated that treatment with Alda-1 reversed alcoholic steatosis and apoptosis by accelerating aldehyde clearance in an animal model of ALD. During lifespan, every organism receives toxic challenge from numerous harmful agents. Some are produced endogenously, while others accumulate after ingestion of food or exposure to environmental pollutants. Organisms have evolved effective protective mechanisms to prevent their propagation, such as: detoxification through enzymatic reactions. Among phase-I oxidizing enzymes, ALDH is a gene superfamily responsible for the detoxification of biogenic and xenogenic aldehydes [[6]Marchitti S.A. Brocker C. Stagos D. Vasiliou V. Non-P450 aldehyde oxidizing enzymes: the aldehyde dehydrogenase superfamily.Expert Opin Drug Metab Toxicol. 2008; 4: 697-720Crossref PubMed Scopus (607) Google Scholar], with the most abundant members, being ALDH2, which is involved in the metabolism of ethanol-derived acetaldehyde and other aldehydes [[6]Marchitti S.A. Brocker C. Stagos D. Vasiliou V. Non-P450 aldehyde oxidizing enzymes: the aldehyde dehydrogenase superfamily.Expert Opin Drug Metab Toxicol. 2008; 4: 697-720Crossref PubMed Scopus (607) Google Scholar], and ALDH1, which has been found to be highly expressed in many adult tissue stem cells or progenitor cells, including hematopoietic, neuron, muscle, hepatic, adipose stem cells, and progenitor cells [7Moreb J.S. Aldehyde dehydrogenase as a marker for stem cells.Curr Stem Cell Res Ther. 2008; 3: 237-246Crossref PubMed Scopus (206) Google Scholar, 8Douville J. Beaulieu R. Balicki D. ALDH1 as a functional marker of cancer stem and progenitor cells.Stem Cells Dev. 2009; 18: 17-25Crossref PubMed Scopus (265) Google Scholar, 9Dollé L. Best J. Empsen C. Mei J. Van Rossen E. Roelandt P. et al.Successful isolation of liver progenitor cells by aldehyde dehydrogenase activity in naive mice.Hepatology. 2012; 55: 540-552Crossref PubMed Scopus (47) Google Scholar]. Aldehydes are widespread organic compounds found in the environment or formed from metabolism of various compounds. Importantly, aldehydes are strong electrophilic compounds that can form adducts with cellular components (i.e. proteins and nucleic acids) thereby initiating adverse biological effects (i.e. loss of protein activity and mutation of nucleic acids) [[10]Singh S. Brocker C. Koppaka V. Chen Y. Jackson B.C. Matsumoto A. et al.Aldehyde dehydrogenases in cellular responses to oxidative/electrophilic stress.Free Radic Biol Med. 2013; 56: 89-101Crossref PubMed Scopus (412) Google Scholar]. Hence, disposal of aldehyde is a priority for cell protection and survival, even more so for long-living cells such as progenitors. Evidence from human phenotypes directly linked to mutations and polymorphisms in ALDH genes, leading to the absence, deficiency or inactivation of ALDH proteins, stress the clinical importance of the ALDH superfamily. Such disorders include type II hyperprolinaemia, Sjögren-Larsson syndrome, alcohol-induced flushing syndrome and others [[6]Marchitti S.A. Brocker C. Stagos D. Vasiliou V. Non-P450 aldehyde oxidizing enzymes: the aldehyde dehydrogenase superfamily.Expert Opin Drug Metab Toxicol. 2008; 4: 697-720Crossref PubMed Scopus (607) Google Scholar]. Diseases caused by mutations in ALDH genes involve the building-up of substances in the body that are harmful in large amounts or that impair the function or production of necessary molecules. Therefore, the use of pharmacological activators or inhibitors of ALDH isoenzymes represents a coherent approach for the treatment of these pathological disorders [[6]Marchitti S.A. Brocker C. Stagos D. Vasiliou V. Non-P450 aldehyde oxidizing enzymes: the aldehyde dehydrogenase superfamily.Expert Opin Drug Metab Toxicol. 2008; 4: 697-720Crossref PubMed Scopus (607) Google Scholar]. Among the 19 human ALDH isoenzymes [6Marchitti S.A. Brocker C. Stagos D. Vasiliou V. Non-P450 aldehyde oxidizing enzymes: the aldehyde dehydrogenase superfamily.Expert Opin Drug Metab Toxicol. 2008; 4: 697-720Crossref PubMed Scopus (607) Google Scholar, 11Vasiliou V. Nebert D.W. Analysis and update of the human aldehyde dehydrogenase (ALDH) gene family.Hum Genomics. 2005; 2: 138-143Crossref PubMed Scopus (311) Google Scholar], ALDH2 (or ALDH2∗1) is described to be the most efficient for the metabolism of ethanol-derived acetaldehyde, but also to carry the most well-known polymorphism (ALDH2∗2) with ALDH2 activity deficiency. Eight percent of the world population have this common polymorphism, which renders the enzyme inactive in vivo [[4]Chen C.H. Ferreira J.C. Gross E.R. Mochly-Rosen D. Targeting aldehyde dehydrogenase 2: new therapeutic opportunities.Physiol Rev. 2014; 94: 1-34Crossref PubMed Scopus (414) Google Scholar]. Accumulation of acetaldehyde after ethanol consumption leads to the development of unpleasant physiological effects comprising facial flushing, nausea, and tachycardia. This condition, termed the alcohol flushing syndrome experienced by persons with the ALDH2∗2 polymorphism, renders a large population of East Asians intolerant of what might be considered "normal" levels of alcohol consumption (see Refs. [4Chen C.H. Ferreira J.C. Gross E.R. Mochly-Rosen D. Targeting aldehyde dehydrogenase 2: new therapeutic opportunities.Physiol Rev. 2014; 94: 1-34Crossref PubMed Scopus (414) Google Scholar, 6Marchitti S.A. Brocker C. Stagos D. Vasiliou V. Non-P450 aldehyde oxidizing enzymes: the aldehyde dehydrogenase superfamily.Expert Opin Drug Metab Toxicol. 2008; 4: 697-720Crossref PubMed Scopus (607) Google Scholar, 12Koppaka V. Thompson D.C. Chen Y. Ellermann M. Nicolaou K.C. Juvonen R.O. et al.Aldehyde dehydrogenase inhibitors: a comprehensive review of the pharmacology, mechanism of action, substrate specificity, and clinical application.Pharmacol Rev. 2012; 64: 520-539Crossref PubMed Scopus (414) Google Scholar]). However, many people with the dominant inactive form of ALDH2∗2 still drink heavily and they have high levels of blood acetaldehyde even after drinking only a moderate amount of alcohol [[13]Enomoto N. Takase S. Yasuhara M. Takada A. Acetaldehyde metabolism in different aldehyde dehydrogenase-2 genotypes.Aging Clin Exp Res. 1991; 15: 141-144Crossref Scopus (247) Google Scholar]. Several studies have examined the role of ALDH2∗2 polymorphism in the pathogenesis of ALD and suggest that ALD patients with inactive ALDH2 had a high risk for the progression of liver disease [14Enomoto N. Takase S. Takada N. Takada A. Alcoholic liver disease in heterozygotes of mutant and normal aldehyde dehydrogenase-2 genes.Hepatology. 1991; 13: 1071-1075Crossref PubMed Scopus (133) Google Scholar, 15Chao Y.C. Liou S.R. Chung Y.Y. Tang H.S. Hsu C.T. Li T.K. et al.Polymorphism of alcohol and aldehyde dehydrogenase genes and alcoholic cirrhosis in Chinese patients.Hepatology. 1994; 19: 360-366Crossref PubMed Scopus (166) Google Scholar, 16Nagata N. Hiyoshi M. Shiozawa H. Shiraishi K. Watanabe N. Tsuda M. et al.Assessment of a difference in ALDH2 heterozygotes and alcoholic liver injury.Alcohol Clin Exp Res. 2002; 26: 11S-14SCrossref PubMed Google Scholar]. To increase the activity of this ALDH2∗2 mutant allele, researchers have developed Alda-1 (or [N-(1,3-benzodioxol-5-ylmethyl)-2,6-dichlorobenzamide]) that acts as a structural chaperone to activate wild-type ALDH2 and restore the mutant ALDH2∗2 to near wild-type activity by aiding in the proper folding of a section of the polypeptide chain that lacks stable structure in its absence, allowing it to break down toxic aldehydes quicker and leaving less time for them to cause damage [[17]Perez-Miller S. Younus H. Vanam R. Chen C.H. Mochly-Rosen D. Hurley T.D. Alda-1 is an agonist and chemical chaperone for the common human aldehyde dehydrogenase 2 variant.Nat Struct Mol Biol. 2010; 17: 159-164Crossref PubMed Scopus (184) Google Scholar]. Interestingly, Alda-1 also increases productive substrate-enzyme interaction, allowing an increase of ALDH2 activity, and protects the wild-type ALDH2 (i.e. ALDH2∗1) from inactivation due to adduct formation between the substrate and the enzyme [17Perez-Miller S. Younus H. Vanam R. Chen C.H. Mochly-Rosen D. Hurley T.D. Alda-1 is an agonist and chemical chaperone for the common human aldehyde dehydrogenase 2 variant.Nat Struct Mol Biol. 2010; 17: 159-164Crossref PubMed Scopus (184) Google Scholar, 18Chen C.H. Budas G.R. Churchill E.N. Disatnik M.H. Hurley T.D. Mochly-Rosen D. Activation of aldehyde dehydrogenase-2 reduces ischemic damage to the heart.Science. 2008; 321: 1493-1495Crossref PubMed Scopus (630) Google Scholar]. The manner in which Alda-1 binds to the structure of ALDH2 provides powerful insight into the relationships between chaperones of this detoxifying enzyme leading to the plausible modification of Alda-1 to improve its potency, but also opens up the possibility of designing new analogs that can selectively affect the metabolism of other molecules that are detoxified by ALDHs [[17]Perez-Miller S. Younus H. Vanam R. Chen C.H. Mochly-Rosen D. Hurley T.D. Alda-1 is an agonist and chemical chaperone for the common human aldehyde dehydrogenase 2 variant.Nat Struct Mol Biol. 2010; 17: 159-164Crossref PubMed Scopus (184) Google Scholar]. The study from Zhong et al. [[5]Zhong W. Zhang W. Li Q. Xie G. Sun Q. Sun X. et al.Pharmacological activation of aldehyde dehydrogenase 2 by Alda-1 reverses alcohol-induced hepatic steatosis and cell death in mice.J Hepatol. 2015; 62: 1375-1381Abstract Full Text Full Text PDF PubMed Scopus (77) Google Scholar] demonstrates that enhancing the ALDH2 activity by the use of Alda-1 can ameliorate several deleterious effects related to aldehydes (Fig. 1) and may provide a better protection against both acute and chronic injury pre-established by chronic alcohol exposure [[5]Zhong W. Zhang W. Li Q. Xie G. Sun Q. Sun X. et al.Pharmacological activation of aldehyde dehydrogenase 2 by Alda-1 reverses alcohol-induced hepatic steatosis and cell death in mice.J Hepatol. 2015; 62: 1375-1381Abstract Full Text Full Text PDF PubMed Scopus (77) Google Scholar]. Indeed, in alcohol intoxicated animals, Alda-1 accelerates plasma and hepatic aldehyde clearances, reduces the level of 4-HNE, reverses steatosis, and diminishes alcohol-induced endoplasmic reticulum stress and apoptosis (Fig. 1). These findings are encouraging, and warrant further investigations in other models of ALD. For example, a recent study reported that ALDH2 deficiency exacerbates alcohol and/or hepatotoxin-induced liver inflammation and fibrosis [[19]Kwon H.J. Won Y.S. Park O. Chang B. Duryee M.J. Thiele G.E. et al.Aldehyde dehydrogenase 2 deficiency ameliorates alcoholic fatty liver but worsens liver inflammation and fibrosis in mice.Hepatology. 2014; 60: 146-157Crossref PubMed Scopus (142) Google Scholar]. Thus it is important to test whether Alda-1 treatment also ameliorates alcoholic liver inflammation and fibrosis. Also, alcohol consumption can disrupt the intestinal epithelial barrier resulting in increased gut permeability, recently documented as a major factor in ALD (see reviews [20Quigley E.M. Stanton C. Murphy E.F. The gut microbiota and the liver. Pathophysiological and clinical implications.J Hepatol. 2013; 58: 1020-1027Abstract Full Text Full Text PDF PubMed Scopus (102) Google Scholar, 21Szabo G. Gut-liver axis in alcoholic liver disease.Gastroenterology. 2015; 148: 30-36Abstract Full Text Full Text PDF PubMed Scopus (514) Google Scholar]). Since acetaldehyde-induced intestinal permeability has been demonstrated [[22]Rao R.K. Seth A. Sheth P. Recent Advances in Alcoholic Liver Disease I. Role of intestinal permeability and endotoxemia in alcoholic liver disease.Am J Physiol Gastrointest Liver Physiol. 2004; 286: G881-G884Crossref PubMed Scopus (296) Google Scholar], and also that microbes and intestinal cells can detoxify alcohol into acetaldehyde, it is legitimate to speculate that these microbes and intestinal cells might also uptake Alda-1 once delivered by intraperitoneal injection (see Table 1 in ref [[5]Zhong W. Zhang W. Li Q. Xie G. Sun Q. Sun X. et al.Pharmacological activation of aldehyde dehydrogenase 2 by Alda-1 reverses alcohol-induced hepatic steatosis and cell death in mice.J Hepatol. 2015; 62: 1375-1381Abstract Full Text Full Text PDF PubMed Scopus (77) Google Scholar]). Consequently, Alda-1 may favorably co-influence the course of aldehyde clearance, liver injury (decrease of ALT, AST) and outcome of ALD acting on gut microbiota. In addition, ALDH1 is highly expressed in liver progenitor cells and is believed to play an important role in promoting liver progenitor cell survival [[9]Dollé L. Best J. Empsen C. Mei J. Van Rossen E. Roelandt P. et al.Successful isolation of liver progenitor cells by aldehyde dehydrogenase activity in naive mice.Hepatology. 2012; 55: 540-552Crossref PubMed Scopus (47) Google Scholar], thus, activation of ALDH by Alda-1 may have beneficial effects for liver repair via the stimulation of liver progenitor cells. However, cancer stem cells also express high levels of ALDH1 [[8]Douville J. Beaulieu R. Balicki D. ALDH1 as a functional marker of cancer stem and progenitor cells.Stem Cells Dev. 2009; 18: 17-25Crossref PubMed Scopus (265) Google Scholar], so it is important to examine whether ALDH activator also affects cancer stem cells and has a risk for promoting liver cancer development and progression. What is the therapeutic potential of ALDH activators such as Alda-1 for the treatment of ALD? Because abstinence is the cornerstone for treatment of ALD, most ALD patients during treatment periods are not active drinkers or are commonly treated with approaches to eliminate alcohol ingestion. Indeed, disulfiram (or Antabuse™), an irreversible inhibitor of ALDH, is commonly prescribed to treat alcoholism to prevent acetaldehyde metabolism, which results in elevation of acetaldehyde and subsequently causes unpleasant effects and aversion to alcohol. Disulfiram is not recommended for patients with advanced ALD due to its potential severe hepatotoxicity. Because ALD patients, who are not active drinkers, most likely have low levels of acetaldehyde, treatment of these patients with Alda-1 may not generate significant beneficial effects. For ALD patients who are active drinkers, treatment with Alda-1 may reduce acetaldehyde levels and consequently ameliorate liver toxicity, but may also have a risk to promote alcohol drinking in these patients. Therefore, the therapeutic potential of ALDH activators for ALD remains to be carefully determined. Alda-1 treatment may have some therapeutic potential to reduce alcohol toxicity in patients with excessive acute alcohol consumption especially in those with inactive ALDH2. Finally, whether treatment with ALDH activators has beneficial effects for other aldehyde accumulation-related diseases deserves further studies. LD: Interuniversity Attraction Pole (IAP) (Institute for Aegean Prehistory) – phase VII – contract P7/47 (Federal Science Policy – BELSPO); BG: the intramural program of National Institute on Alcohol Abuse and Alcoholism, NIH. The authors declared that they do not have anything to disclose regarding funding or conflict of interest with respect to this manuscript. We are grateful to Professor Thomas D. Hurley (Department of Biochemistry and Molecular Biology Indiana University School of Medicine, USA) for his valuable input on pharmacological chaperones and its passionate discussion about the importance of the modulators of ALDHs.