Ethanol is first metabolized primarily by alcohol dehydrogenase (ADH) into acetaldehyde (Figure 2), a mutagen and animal carcinogen that causes DNA damage and has other cancer-promoting effects [5–7]. Acetaldehyde is subsequently metabolized to acetate, mainly by the enzyme ALDH2 [8]. In East Asian populations there are two main variants of ALDH2, resulting from the replacement of glutamate (Glu) at position 487 with lysine (Lys) [9]. The Glu allele (also designated ALDH2*1) encodes a protein with normal catalytic activity, whereas the Lys allele (ALDH2*2) encodes an inactive protein. As a result, Lys/Lys homozygotes have no detectable ALDH2 activity. Because the Lys allele acts in a semi-dominant manner, ALDH2 Lys/Glu heterozygotes have far less than half of the ALDH2 activity of Glu/Glu homozygotes; in fact, the reduction in ALDH2 activity in heterozygotes is more than 100-fold [8].
