Diseases Associated with Acetaldehyde Toxicity

Alcohol Metabolism Deficiency (ALMD)

Pharmacokinetic and pharmacodynamics basis for overcoming acetaldehyde-induced adverse reaction in Asian alcoholics, heterozygous for the variant ALDH2*2 gene allele.

Chen YC, Peng GS, Tsao TP, Wang MF, Lu RB, Yin SJ. Pharmacogenetics and Genomics 2009


Refined geographic distribution of the oriental ALDH2*504Lys (nee 487Lys) variant.

Li H, Borinskaya S, Yoshimura K, Kal'ina N, Marusin A, Stepanov, VA, Qin Z, Khaliq S, Lee MY, Yang Y Mohyuddin A, Gurwitz D, Mehdi QS, Rogaev E, Jin L, Yankovsky NK, Kidd JR, Kidd KK.

Annals of Human Genetics (2009) 73, 335-345.


Cancer

Carcinogenicity of alcoholic beverages.

Baan R, Straif K, Grosse Y, Secretan B, El Ghissassi F, Bouvard V, Altieri A, Cogliano V; WHO International Agency for Research on Cancer Monograph Working Group.

Lancet Oncol. 2007 Apr; 8(4):292-3

PMID:17431955


The alcohol flushing response: an unrecognized risk factor for esophageal cancer from alcohol consumption.

Brooks PJ, Enoch MA, Goldman D, Li TK, Yokoyama A., PLoS Med. 2009;6(3):e50.

PMID: 19320537


Genetic modulation of ADH1B and ALDH2 polymorphisms with regard to alcohol and tobacco consumption for younger aged esophageal squamous cell carcinoma diagnosis.

Lee CH, Wu DC, Wu IC, Goan YG, Lee JM, Chou SH, Chan TF, Huang HL, Hung YH, Huang MC, Lai TC, Wang TN, Lan CC, Tsai S, Lin Wy, Wu MT. Int. J. Cancer. 2009; 125, 1134-1142.


Fanconi Anemia

Genotoxic consequences of endogenous aldehydes on mouse haematopoietic stem cell function.

Garaycoechea JI, Crossan GP, Langevin F, Daly M, Arends MJ, Patel KJ. Nature. 2012; 489(7417):571-5.

PMID: 22922648


Fancd2 counteracts the toxic effects of naturally produced aldehydes in mice.

Langevin F, Crossan GP, Rosado IV, Arends MJ, Patel KJ. Nature. 2011; 475(7354):53-8.

PMID: 21734703


Stressed out: endogenous aldehydes damage hematopoietic stem cells.

Parmar K and D'Andrea AD Cell Stem Cell 11 2012.


Variant ALDH2 is associated with accelerated progression of bone marrow failure in Japanese Fanconi anemia patients.

Hira A, Yabe H, Yoshida K, Okuno Y, Shiraishi Y, Chiba K, Tanaka H, Miyano S, Nakamura J, Kojima S, Ogawa S, Matsuo K, Takata M and Yabe M. Blood. 2013 Oct 31; 122 (18):3206-9.


Other Diseases:

The role of acetaldehyde in the actions of alcohol (update 2000).

Eriksson CJ. Alcohol Clin Exp Res. 2001; 25(5 Suppl ISBRA):15S-32S.

PMID:11391045


Putative role of brain acetaldehyde in ethanol addiction.

Den XS, Deitrich RA. Curr Drug Abuse Rev. 2008; 1(1): 3-8.


Non-P450 aldehyde oxidizing enzymes: the aldehyde dehydrogenase superfamily

Marchitti SA, Brocker C, Stagos D, and Vasiliou V.

Expert Opin Drug Metab Toxicol. 2008 June

PMC 2009 March 19


Aldehyde Dehydrogenase Superfamily:

Analysis and update of the human aldehyde dehydrogenase (ALDH) gene family.

Vasiliou V, Nebert D.

Human Genomics. 2005. 2(2): 138-143.

Update on the aldehyde dehydrogenase gene (ALDH) superfamily.

Jackson B, Brocker C, Thompson DC, Black W, Vasiliou K, Nebert D, Vasiliou V.

Human Genomics. 2011. 5(4): 283-303.


Potential therapeutic effect of ALDH activators or inhibitors in disease models (cell or animal)

Activators

Ischemia-reperfusion injuries/organ protection:


Activation of aldehyde dehydrogenase-2 reduces ischemic damage to the heart.

Chen CH, Budas GR, Churchill EN, Disatnik MH, Hurley TD, Mochly-Rosen D.

Science. 2008; 321(5895):1493-5.

PMID: 18787169


Activation of aldehyde dehydrogenase 2 (ALDH2) confers cardioprotection in protein kinase C epsilon (PKCvarepsilon) knockout mice.

Budas GR, Disatnik MH, Chen CH, Mochly-Rosen DJ Mol Cell Cardiol. 2010; 48(4):757-64. PMID:19913552


Aldehyde dehydrogenase activation prevents reperfusion arrhythmias by inhibiting local renin release from cardiac mast cells.

Koda K, Salazar-Rodriguez M, Corti F, Chan NY, Estephan R, Silver RB, Mochly-Rosen D, Levi R.

Circulation. 2010; 122(8):771-81.

PMID: 20697027


Aldehyde Dehydrogenase-2 Activation during Cardioplegic Arrest Enhances the Cardioprotection against Myocardial Ischemia-Reperfusion Injury.

Gong D, Zhang Y, Zhang H, Gu H, Jiang Q, Hu S.

Cardiovasc Toxicol. 2012; 12(4):350-8.

PMID:22814936


Protection against Angiotensin II-Induced Cardiac Remodeling and Myocardial Dysfunction:


Mitochondrial Aldehyde Dehydrogenase 2 (ALDH2) Ameliorates Angiotensin II-Induced Cardiac Remodeling and Myocardial Dysfunction through Inhibition of Mitochondrial Oxidative Stress and Induction of Autophagy

Yingmei Zhang, Jun Ren

Poster: American Heart Association, 2012 annual conference


Protection against ethanol-induced cardiac toxicity:


AMP-dependent kinase and autophagic flux are involved in aldehyde dehydrogenase-2-induced protection against cardiac toxicity of ethanol.

Ge W, Guo R, Ren J.

Free Radic Biol Med. 2011; 51(9):1736-48.

PMID: 21871561


Overcoming nitroglycerin inhibition:


ALDH2 activator inhibits increased myocardial infarction injury by nitroglycerin tolerance.

Sun L, Ferreira JC, Mochly-Rosen D.

Sci Transl Med. 2011; 3(107):107ra111.

PMID: 22049071


Diabetic cardiomyopathy:


Mitochondrial aldehyde dehydrogenase (ALDH2) protects against streptozotocin-induced diabetic cardiomyopathy: role of GSK3β and mitochondrial function.

Zhang Y, Babcock SA, Hu N, Maris JR, Wang H, Ren J.

BMC Med. 2012; 10:40.

PMID: 22524197


Radiation dermatitis:


Mitigation of radiation-induced dermatitis by activation of aldehyde dehydrogenase 2 using topical alda-1 in mice.

Ning S, Budas GR, Churchill EN, Chen CH, Knox SJ, Mochly-Rosen D.

Radiat Res. 2012 Jul;178(1):69-74. Epub 2012 Mar 9.

PMID: 22404739


Parkinson's disease:


Identification of aldehyde dehydrogenase 1A1 modulators using virtual screening.

Kotraiah V, Pallares D, Toema D, Kong D, Beausoleil E.

J Enzyme Inhib Med Chem. 2012

PMID: 22380773


Salivary gland stem cell enrichment:


A novel aldehyde dehydrogenase-3 activator leads to adult salivary stem cell enrichment in vivo.

Banh A, Xiao N, Cao H, Chen CH, Kuo P, Krakow T, Bavan B, Khong B, Yao M, Ha C, Kaplan MJ, Sirjani D, Jensen K, Kong CS, Mochly-Rosen D, Koong AC, Le QT.

Clin Cancer Res. 2011; 17(23):7265-72.

PMID:21998334


Inhibitors:

ALDH2 inhibition reduces addiction:


Inhibition of aldehyde dehydrogenase-2 suppresses cocaine seeking by generating THP, a cocaine use-dependent inhibitor of dopamine synthesis.

Yao L, Fan P, Arolfo M, Jiang Z, Olive MF, Zablocki J, Sun HL, Chu N, Lee J, Kim HY, Leung K, Shryock J, Blackburn B, Diamond I.

Nat Med. 2010; 16(9):1024-8.

PMID: 20729865


A selective ALDH-2 inhibitor reduces anxiety in rats.

Overstreet DH, Knapp DJ, Breese GR, Diamond I.

Pharmacol Biochem Behav. 2009; 94(2):255-61.

PMID: 19747934


Suppression of heavy drinking and alcohol seeking by a selective ALDH-2 inhibitor.

Arolfo MP, Overstreet DH, Yao L, Fan P, Lawrence AJ, Tao G, Keung WM, Vallee BL, Olive MF, Gass JT, Rubin E, Anni H, Hodge CW, Besheer J, Zablocki J, Leung K, Blackburn BK, Lange LG, Diamond I.

Alcohol Clin Exp Res. 2009; 33(11):1935-44.

PMID: 19673742


Structure of daidzin, a naturally occurring anti-alcohol-addiction agent, in complex with human mitochondrial aldehyde dehydrogenase.

Lowe ED, Gao GY, Johnson LN, Keung WM.

J Med Chem. 2008; 51(15):4482-7.

PMID: 18613661


Potential role of ALDH inhibition in cancer:


High Aldehyde Dehydrogenase Activity Enhances Stem Cell Features in Breast Cancer Cells by Activating Hypoxia-Inducible Factor-2α

Kim RJ, Park JR, Roh KJ, Choi AR, Kim SR, Kim PH, Yu JH, Lee JW, Ahn SH, Gong G, Hwang JW, Kang KS, Kong G, Sheen YY, Nam JS.

Cancer Lett. 2012 Nov 19.

PMID: 23174107


Inhibition of aldehyde dehydrogenase (ALDH) activity reduces chemotherapy and radiation resistance of stem-like ALDHhiCD44⁺ human breast cancer cells.

Croker AK, Allan AL.

Breast Cancer Res Treat. 2012 May; 133(1):75-87.

PMID:21818590


Cytotoxic effect of disulfiram/copper on human glioblastoma cell lines and ALDH-positive cancer-stem-like cells.

Liu P, Brown S, Goktug T, Channathodiyil P, Kannappan V, Hugnot JP, Guichet PO, Bian X, Armesilla AL, Darling JL, Wang W.

Br J Cancer. 2012; 107(9):1488-97.

PMID:23033007


Review for ALDH inhibitors:


Aldehyde dehydrogenase inhibitors: a comprehensive review of the pharmacology, mechanism of action, substrate specificity, and clinical application.

Koppaka V, Thompson DC, Chen Y, Ellermann M, Nicolaou KC, Juvonen RO, Petersen D, Deitrich RA, Hurley TD, Vasiliou V.

Pharmacol Rev. 2012; 64(3):520-39.

PMID: 22544865


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