The aldehyde dehydrogenase (ALDH) inhibitor cyanamide was used to mimic the effect of prolonged acetaldehyde exposure because acetaldehyde is quickly degraded by ALDH.
Because the rs671 Lys allele causes ALDH2 inactivation leading to increased acetaldehyde exposure, the observed inverse genetic association with mucinous ovarian cancer is inferred to mean that alcohol intake may be a risk factor for this histotype.
The aldehyde dehydrogenase 2 (ALDH2) polymorphism rs671 (Glu504Lys) causes ALDH2 inactivation and adverse acetaldehyde exposure among Asians, but little is known of the association between alcohol consumption and rs671 and ovarian cancer (OvCa) in Asians.
A closer inspection of genome-wide metabolic fluxes revealed several reactions were involved in futile cycles to produce excess acetaldehyde.
These data collectively demonstrate that excess acetaldehyde from endogenous or exogenous sources results in severe toxicity in the absence of FANCD2 (Langevin et al., 2011).
Even under normal physiologic conditions, this process produces excess acetaldehyde, reactive oxygen species (ROS) and other harmful adducts inducing oxidative stress [ 15].
In addition to acetylation, ethanol and acetaldehyde exposure also promotes phosphorylation of histone H3 at serines 10 and 28 (Lee and Shukla 2007).
Interestingly, intensification of acetaldehyde flux-sum beyond a certain point in wild-type decreases the ethanol production as the excess acetaldehyde gets converted into acetate via aldehyde dehydrogenase and then into acetyl-CoA via phosphotransacetylase (PTA) and acetate kinase (ACK), forming a cycle.
It might be hypothesized that this finding reflects a genotype environment correlation where ALDH2 and ADH1B variants influence the likelihood of continued alcohol (and acetaldehyde) exposure, which, in turn, serves as the environmental risk factor for the development of esophageal cancer, either as a result of prolonged ethanol exposure or of the carcinogenic effects of acetaldehyde.
Approximately half of the Japanese individuals were found to have a deficient phenotype for aldehyde dehydrogenase-2, a key enzyme in the conversion of acetaldehyde to acetate (Agarwal et al, 1981; Shibuya and Yoshida, 1988), resulting in higher levels of acetaldehyde exposure, which is considered to be carcinogenic (IARC, 1988).
