Impairment of pyruvate dehydrogenase activity by acetaldehyde and fetal alcohol syndrome

The facial features that are characteristic of alcohol related birth defects (ARBD) are remarkably similar to those seen in pyruvate dehydrogenase (PDH) deficiency. The relative contribution of ethanol or its first oxidized metabolite, acetaldehyde (AcH), to the teratogenesis still is not known. We have found that only 35% (95% CI: 21-41%) of heavy drinkers will have a child with an ARBD, which may be associated with the fact that only 38% (95% CI: 11-66%) of chronic alcoholics will have high AcH levels. The purpose of this work was to examine the effect of AcH on PDH in vitro. The activity of PDH was measured in the presence of AcH (10 μM-1 mM) by measuring the formation of NADH at 340 nm. PDH was also incubated with [1,2-¹⁴C]-AcH to detect the formation of covalent adducts using SDS-PAGE. The results show that AcH impairs PDH activity by a mixed inhibition type mechanism (Kic=62.4±25.7 μM, Kiu=225±68 μM) and although AcH is capable of forming covalent adducts with PDH this does not contribute to the inhibition. Because PDH levels are low throughout development and the competition between pyruvate and AcH may be enhanced due to ethanol induced lowering of ambient pyruvate concentrations, we conclude that impairment of PDH may have a significant effect on the developing fetus.