Aldehyde dehydrogenase deficiency as cause of facial flushing reaction to alcohol in Japanese.

A dehydrogenase is an enzyme responsible for the breakdown of acetaldehyde, a toxic intermediate1 produced directly from the metabolism of alcohol. Aldehyde dehydrogenase is extraordinarily efficient in keeping acetaldehyde levels very low, even immediately after alcohol consumption when acetaldehyde is being generated rapidly in the liver. Multiple aldehyde dehydrogenase enzymes exist and their structures are determined by different genes; however, this commentary examines only the enzyme (designated as ALDH2) that is imported into the mitochondrion, the cell’s energy­ producing structure. The seminal ar­ ticle by Harada and colleagues, which actually is a detailed letter to the editor of the journal Lancet, first related the discovery of the effect of a genetic variant of this enzyme, which occurs very abundantly in Oriental populations (East Asians). ALDH2 is key in the metabolism of acetaldehyde produced after alco­ hol consumption. In 1948 Hald and Jacobsen introduced disulfiram (Antabuse®), an inhibitor of alde­ hyde dehydrogenase, for the clinical treatment of alcoholics. Disulfiram­ treated subjects who consume alco­ hol accumulate relatively high levels of acetaldehyde. These high acet­ aldehyde levels lead to an aversive response known as the flushing reac­ tion. In addition to a facial flush, the flushing reaction also may include an elevated heart rate (i.e., tachycar­ dia), headache, heart palpitations, shortness of breath (i.e., dyspnea), hyperventilation, low blood pressure (i.e., hypotension), vertigo, nausea, and vomiting. Certain other drugs that also inhibit aldehyde dehydroge­ nase, such as metronidazole, were found to cause flushing in associa­ tion with alcohol intake. This flush­ ing reaction also occurs naturally in some people. However, the blockade of aldehyde dehydrogenase actually was used to treat alcoholism long be­ fore the mechanism that causes natu­ rally occurring alcohol­induced flushing was discovered. Harada and colleagues directly related naturally occurring aldehyde dehydrogenase blockade to elevated acetaldehyde lev­ els and flushing. Wolff (1972) and others (Zeiner et al. 1979) had observed that unmedicated Japanese and people from neigh­ boring regions of Asia often showed the same flushing response after intake of relatively small quantities of alcohol. In 1981 Harada and colleagues Agarwal and Goedde showed that some people were naturally deficient in the aldehyde dehydrogenase enzyme (Agarwal et al. 1981). By using a technique (i.e., protein electrophoresis) that separates the enzyme in an electric field, followed by a stain for the enzyme, they found that acetaldehyde dehydrogenase was structurally different in people in whom the aldehyde dehydrogenase activity was deficient. One year later these researchers published their seminal letter to the editor of