title: Pharmacological recruitment of aldehyde dehydrogenase 3A1 (ALDH3A1) to assist ALDH2 in acetaldehyde and ethanol metabolism in vivo.
abstract: Correcting a genetic mutation that leads to a loss of function has been a challenge. One such mutation is in aldehyde dehydrogenase 2 (ALDH2), denoted ALDH2*2. This mutation is present in ∼ 0.6 billion East Asians and results in accumulation of toxic acetaldehyde after consumption of ethanol. To temporarily increase metabolism of acetaldehyde in vivo, we describe an approach in which a pharmacologic agent recruited another ALDH to metabolize acetaldehyde. We focused on ALDH3A1, which is enriched in the upper aerodigestive track, and identified Alda-89 as a small molecule that enables ALDH3A1 to metabolize acetaldehyde. When given together with the ALDH2-specific activator, Alda-1, Alda-89 reduced acetaldehyde-induced behavioral impairment by causing a rapid reduction in blood ethanol and acetaldehyde levels after acute ethanol intoxication in both wild-type and ALDH2-deficient, ALDH2*1/*2, heterozygotic knock-in mice. The use of a pharmacologic agent to recruit an enzyme to metabolize a substrate that it usually does not metabolize may represent a novel means to temporarily increase elimination of toxic agents in vivo.
authors.affiliation: Department of Chemical and Systems Biology, Stanford University, School of Medicine, Stanford, CA 94305-5174.
authors.forename: Che-Hong
authors.initials: CH
authors.lastname: Chen
authors.affiliation: Department of Chemical and Systems Biology, Stanford University, School of Medicine, Stanford, CA 94305-5174.
authors.forename: Leslie A
authors.initials: LA
authors.lastname: Cruz
authors.affiliation: Department of Chemical and Systems Biology, Stanford University, School of Medicine, Stanford, CA 94305-5174 mochly@stanford.edu.
authors.forename: Daria
authors.initials: D
authors.lastname: Mochly-Rosen
mesh_terms: D000444:Aldehyde Dehydrogenase / Q000187:drug effects* / Q000378:metabolism*; D000071396:Aldehyde Dehydrogenase, Mitochondrial; D000818:Animals; D000431:Ethanol / Q000378:metabolism*; D006801:Humans; D051379:Mice; D008822:Mice, Transgenic; D011485:Protein Binding
chemical_list: D000431:Ethanol; C515029:ALDH2 protein, mouse; C480021:ALDH3A1 protein, human; D000444:Aldehyde Dehydrogenase; D000071396:Aldehyde Dehydrogenase, Mitochondrial
keywords: ALDH2; ALDH3A1; Alda; acetaldehyde; ethanol metabolism