Altering substrate specificity of aldehyde dehydrogenase 3A1 to enhance acetaldehyde metabolism, in vivo (585.9)

Acetaldehyde is a well‐know cytotoxin, and carcinogen. Detoxification of acetaldehyde, which is mainly carried out by the mitochondrial aldehyde dehydrogenase 2 (ALDH2), is crucial to human health. High levels of acetaldehydes are present in the saliva and in circulation after ethanol ingestion and likely contribute to the high incidence of esophageal cancer in alcoholics and in carriers of a common ALDH2 mutation (ALDH2*2) found in 540 million East Asians. Acetaldehyde is also partly responsible for behavior impairment following ethanol consumption. Therefore, means to accelerate acetaldehyde clearance will be beneficial for human health. We previously identified an activator of ALDH2 that accelerated acetaldehyde metabolism. Here we describe the recruitment of an additional ALDH isozyme, ALDH3A1, to accelerate the clearance of acetaldehyde by the use of a small molecule. ALDH2 is the main isozyme that metabolizes acetaldehyde in liver. In contrast, ALDH3A1, which is present in the stomach and mucosa of the esophagus, normally metabolizes aromatic aldehydes and is ineffective in metabolizing acetaldehyde. We identified a small molecule activator, Alda‐89, which increased the Kcat of ALDH3A1 for acetaldehyde and enhanced its catalysis. We showed that when given together with an ALDH2‐specific activator, Alda‐1, Alda‐89 induced a rapid reduction in blood ethanol and acetaldehyde levels after acute ingestion of ethanol in mice. Importantly, treatment with Alda‐1 and Alda‐89 also reduced behavioral impairment in both wild‐type and ALDH2*2 mice. The ability to recruit an enzyme to metabolize a substrate that it usually does not metabolize using a pharmacological agent may represent a novel strategy to increase metabolism of toxic agents, in vivo. Grant Funding Source : Supported by NIH AA11147 to DM‐R