Impairment of pyruvate dehydrogenase activity by acetaldehyde

The facial features that are characteristic of fetal alcohol syndrome (FAS) are strikingly similar to those seen in pyruvate dehydrogenase (PDH) defic iency. Furthermore, alcohol-induced central nervous system insult results i n midline anomalies such as agenesis of the corpus callosum, which has also been described in several metabolic diseases, including PDH deficiency. Th e purpose of this work was to examine the effect of acetaldehyde on PDH in vitro. The activity of PDH was measured in the presence of acetaldehyde (10 muM-1 mM) by measuring the formation of the reduced form of nicotinamide-a denine dinucleotide at 340 nm. Pyruvate dehydrogenase was separated by usin g the sodium dodecyl sulfate-polyacrylamide gel electrophoresis technique a fter incubation with [1,2-C-14]-acetaldehyde to detect the formation of cov alent adducts autoradiographically. The effect of acetaldehyde on the phosp horylation of the complex was also determined autoradiographically after in cubating of PDH with P-32-adenosine triphosphate. The results of this study show that acetaldehyde impairs PDH activity by a mixed inhibition type mec hanism (Kic = 62.4 +/- 25.7 muM, Kiu = 225 +/- 68 muM), which is not a resu lt of the formation of covalent adducts with PDH, nor of a stimulation of p hosphorylation or inactivation of the complex. Because PDH levels are low t hroughout development and that the competition between pyruvate and acetald ehyde may be enhanced due to ethanol-induced lowering of ambient pyruvate c oncentrations, we conclude that impairment of PDH may have a significant ef fect on the developing fetus. (C) 2001 Elsevier Science Inc. All rights res erved.