Subcellular Localization of Acetaldehyde Oxidation in Liver a

In the past few years there has been an increased interest in the role of acetaldehyde in alcohol-related problems. The enzymes responsible for the metabolism of the compounds have been studied in detail only for the past decade, compared to the alcohol metabolizing enzymes, which have been investigated since the 1950s. Three older review articles are recommended for general reference to acetaldehyde-related problems.’” This article will not focus on any of the physiological or pharmacological effects of acetaldehyde, but only on its subcellular metabolism; an article in 1985 reviews many of those aspects of the p r ~ b l e m . ~ While ethanol oxidizing enzymes are primarily localized in liver, those involved in acetaldehyde oxidation are ubiquitous to the body. Inasmuch as blood acetaldehyde levels are extremely low (pM) even in the presence of relatively high blood ethanol levels, the bulk of the acetaldehyde oxidation must then be confined to liver, where ethanol is primarily converted to the aldehyde. In fact, it has been estimated that, a t least for rats, ca 95% of acetaldehyde oxidation occurs in A number of enzymes are capable of oxidizing acetaldehyde to acetate, the most important one being aldehyde dehydrogenase (ALDH), an NAD-dependent enzyme found in cytosol, endoplasmic reticulum, and mitochondria. Other dehydrogenases such as succinic semialdehyde and glyceraldehyde-3-phosphate dehydrogenase6 can, in vitro. oxidize acetaldehyde. Furthermore, an enzyme misnamed “aldehyde oxidase” can also catalyze the in-vitro oxidation of acetaldehyde.’ This enzyme, like the others, has a very high K, for the compound in contrast to mitochondrial aldehyde dehydrogenase, which has a K, value typically in the pM range. In rodents, many isozymes of liver aldehyde dehydrogenase exist. In man, it appears that there is only one form in each subcellular organelle. Unlike human liver alcohol dehydrogenase, where numerous polymorphic forms of the enzyme exist, only two forms of human mitochondrial ALDH have been described thus far. All people examined have the same cytoplasmic isozyme of ALDH. This enzyme, called “El” by some investigators and “E-11” by others: has a K, for acetaldehyde of ca 200 pM and is very susceptible to inhibition by the antialcohol drug disulfiram (Antabuse), which is often prescribed to deter alcoholics from drinking?.” It is mitochondrial ALDH that has an altered primary sequence in different populations. Basically, the two forms of the enzyme differ from each other by just one amino acid resulting from a single base change in DNA. A guanine being mutated to