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) deficiency. Furthermore, alcohol-induced central nervous system insult results in midline anomalies such as agenesis of the corpus callosum, which has also been described in several metabolic diseases, including PDH deficiency. The 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 microM-1 mM) by measuring the formation of the reduced form of nicotinamide-adenine dinucleotide at 340 nm. Pyruvate dehydrogenase was separated by using the sodium dodecyl sulfate-polyacrylamide gel electrophoresis technique after incubation with [1,2-(14)C]-acetaldehyde to detect the formation of covalent adducts autoradiographically. The effect of acetaldehyde on the phosphorylation of the complex was also determined autoradiographically after incubating of PDH with (32)P-adenosine triphosphate. The results of this study show that acetaldehyde impairs PDH activity by a mixed inhibition type mechanism (Kic=62.4+/-25.7 microM, Kiu=225+/-68 microM), which is not a result of the formation of covalent adducts with PDH, nor of a stimulation of phosphorylation or inactivation of the complex. Because PDH levels are low throughout development and that the competition between pyruvate and acetaldehyde 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.
Hard
M L
ML
Division of Clinical Pharmacology and Toxicology, The Hospital for Sick Children, 555 University Avenue, Toronto, Ontario, Canada M5G 1X8.
Raha
S
S
Spino
M
M
Robinson
B H
BH
Koren
G
G
D000079:Acetaldehyde / Q000494:pharmacology*; D000818:Animals; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D007700:Kinetics; D009206:Myocardium / Q000201:enzymology; D010766:Phosphorylation / Q000187:drug effects; D011768:Pyruvate Dehydrogenase Complex / Q000037:antagonists & inhibitors*; D013552:Swine
D004791:Enzyme Inhibitors; D011768:Pyruvate Dehydrogenase Complex; D000079:Acetaldehyde