Acetaldehyde is responsible for the facial flushing and other unpleasant effects that ALDH2-deficient individuals experience when they drink alcohol [10]. Importantly, there is now direct evidence that ALDH2-deficient individuals experience higher levels of acetaldehyde-related DNA and chromosomal damage than individuals with fully active ALDH2 when they consume equivalent amounts of alcohol, providing a likely mechanism for the increased cancer risk. A study in Japanese alcoholics [17] showed that the amount of mutagenic acetaldehyde-derived DNA adducts (Figure 4) in white blood cells was significantly higher in ALDH2-deficient heterozygotes than in individuals with active ALDH2 (Table 1). In this study, while the two groups were matched for alcohol consumption, the ALDH2-deficient group consumed slightly less alcohol on average than the controls. Also, ALDH2 heterozygotes who drank alcohol had higher levels of white blood cells with chromosomal damage than drinkers with active ALDH2 [18]. Because of these as well as other data, the 2007 International Agency for Research on Cancer Working Group on alcohol and cancer specifically noted the substantial mechanistic evidence supporting a causal role for acetaldehyde in alcohol-related esophageal cancer [19].
