Alcohol dependence was one of the first disorders to be associated with a genetic contribution. In 1972, facial flushing and decreased tolerance after alcohol exposure was observed in subjects of Asian ancestry (Wolff 1972)—a response that is associated with characteristic alterations in alcohol metabolism. Upon ingestion and absorption into the blood stream, alcohol first is converted to acetaldehyde in the liver in a process catalyzed by the enzyme alcohol dehydrogenase (ADH). Acetaldehyde is a highly toxic cancer-inducing substance (i.e., carcinogen) that normally is converted rapidly to acetate, a less toxic form. This reaction is mediated by the mitochondrial enzyme aldehyde dehydrogenase (ALDH). In this metabolic chain of events, two basic mechanisms can result in the accumulation of acetaldehyde in the body—faster metabolism of alcohol to acetaldehyde, which is related to increased ADH activity, and/or slower metabolism of acetaldehyde to acetate, which is caused by decreased ALDH activity. The excessive production and accumulation of acetaldehyde then results in the flushing response, which may be accompanied by lightheadedness, nausea, accelerated heart rate, and headaches. Because of the unpleasantness of this reaction, people experiencing flushing typically drink little or no alcohol.
