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Key Event Title
Inhibition of ALDH1A (RALDH)
|Level of Biological Organization|
Key Event Components
Key Event Overview
AOPs Including This Key Event
|AOP Name||Role of event in AOP||Point of Contact||Author Status||OECD Status|
|Inhibition of ALDH1A leading to reduced fertility||MolecularInitiatingEvent||Terje Svingen (send email)||Under development: Not open for comment. Do not cite||Under Development|
|RALDH2 and cardiovascular developmental defects||MolecularInitiatingEvent||Gina Mennen (send email)||Open for comment. Do not cite|
|All life stages||High|
Key Event Description
The oxidation of retinal to all-trans retinoic acid (atRA) is an irreversible reaction carried out by retinaldehyde dehydrogenases ALDH1A1, ALDH1A2, ALDH1A3 (RALDH1, RALDH2, RALDH3). ALDH1A2 is responsible for the second step of the metabolism of vitamin A into atRA (Chatzi et al, 2013; Shannon et al, 2017).The role of that reaction is to maintain atRA concentrations, with ALDH1A2 being most active during early development (Koppaka et al, 2012; Shannon et al, 2017). Raldh2-deficient mice exhibit severe developmental defects due to loss of atRA, but the phenotype is rescued by administration of exogenous RA (Niederreither et al, 1999). Thus, ALDH1A2 activity is essential for atRA-dependent developmental processes.
How It Is Measured or Detected
There are no OECD validated assays for measuring ALDH1A2 inhibition.
ALDH1A2 mRNA and protein levels can be measured using various probes, antibodies as well as ELISA kits that are commercially available.
Enzyme activity can be assessed in assays including measurement of atRA formation (Arnold et al, 2015) or NADH formation (Harper et al, 2018; Schindler et al, 1998) and several ALDH activity assay kits using different approaches are commercially available; e.g. AldeflourTM kit (Flahaut et al, 2016).
Domain of Applicability
The retinoid signaling system is highly conserved across distant animal species (Bushue & Wan, 2010; Rhinn & Dollé, 2012).
Allen EMG, Anderson DGR, Florang VR, Khanna M, Hurley TD, Doorn JA (2010) Relative inhibitory potency of molinate and metabolites with aldehyde dehydrogenase 2: implications for the mechanism of enzyme inhibition. Chem Res Toxicol 23: 1843-1850
Arnold SL, Kent T, Hogarth CA, Schlatt S, Prasad B, Haenisch M, T. W, Muller CH, Griswold MD, Amory JK, Isoherranen N (2015) Importance of ALDH1A enzymes in determining human testicular retinoic acid concentrations. J Lipid Res 56: 342-357
Bushue N, Wan YJY (2010) Retinoid pathway and cancer therapeutics. Adv Drug Deliv Rev 62: 1285-1298
Chatzi C, Cunningham TJ, Duester G (2013) Investigation of retinoic acid function during embryonic brain development using retinaldehyde-rescued Rdh10 knockout mice. Dev Dyn 242: 1056-1065
Chen Y, Zhu JY, Hong KH, Mikles DC, Georg GI, Goldstein AS, Amory JK, Schönbrunn E (2018) Structural Basis of ALDH1A2 Inhibition by Irreversible and Reversible Small Molecule Inhibitors. ACS Chem Biol 13: 582-590
Flahaut M, Jauquier N, Nardou K, Bourloud KB, Joseph JM, Barras D, Widmann C, Gross N, Renella R, Mühlethaler-Mottet A (2016) Aldehyde dehydrogenase activity plays a Key role in the aggressive phenotype of neuroblastoma. BMC Cancer 16: 781
Harper AR, Le AT, Mather T, Burgett A, Berry W, Summers JA (2018) Design, synthesis, and ex vivo evaluation of a selective inhibitor for retinaldehyde dehydrogenase enzymes. Bioorg Med Chem 26: 5766-5779
Koppaka V, Thompson DC, Chen Y, Ellermann M, Nicolaou KC, Juvonen RO, Petersen D, Deitrich RA, Hurley TD, Vasilio V (2012) Aldehyde dehydrogenase inhibitors: a comprehensive review of the pharmacology, mechanism of action, substrate specificity, and clinical application. Pharmacol Rev 64: 520-539
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Niederreither K, Subbarayan V, Dollé P, Chambon P (1999) Embryonic retinoic acid synthesis is essential for early mouse post-implantation development. Nat Genet 21: 444-448
Paik J, Haenisch M, Muller CH, Goldstein AS, Arnold S, Isoherranen N, Brabb T, Treuting PM, Amory JK (2014) Inhibition of retinoic acid biosynthesis by the bisdichloroacetyldiamine WIN 18,446 markedly suppresses spermatogenesis and alters retinoid metabolism in mice. J Biol Chem 289: 15104-15117
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Rhinn M, Dollé P (2012) Retinoic acid signalling during development. Development 139: 843-858
Schindler JF, Berst KB, Plapp BV (1998) Inhibition of human alcohol dehydrogenases by formamides. J Med Chem 41: 1696-1701
Shannon SR, Moise AR, Trainor PA (2017) New insights and changing paradigms in the regulation of vitamin A metabolism in development. Wiley Interdiscip Rev Dev Biol 6: 10.1002/wdev.1264
Shirota FN, DeMaster EG, Nagasawa HT (1987) Cyanide is a product of the catalase-mediated oxidation of the alcohol deterrent agent, cyanamide. Toxicol Lett 37: 7-12
Staub RE, Quistad GB, Casida JE (1998) Mechanism for benomyl action as a mitochondrial aldehyde dehydrogenase inhibitor in mice. Chem Res Toxicol 11: 535-543