A hypothesis linking hypoglycemia, hyperuricemia, lactic acidemia, and reduced gluconeogenesis in alcoholics to inactivation of glucose-6-phosphatase activity by acetaldehyde.
Preliminary data have been obtained indicating that glucose-6-phosphatase is inactivated upon preincubation with 447 and 224 mM acetaldehyde for 30 min at room temperature, resulting in a loss of 67% and 33% of the original activity, respectively. The reaction with acetaldehyde is rapid because 44% of the enzymic activity is lost in 5 min. Comparable quantities of ethanol inhibit the enzyme to the extent of 11%, indicating a very slight, statistically insignificant organic solvent effect. Because chronic alcoholics present a clinical picture of hypoglycemia, hyperuricemia, reduced gluconeogenesis, and lactic acidemia, it is hypothesized that glucose-6-phosphatase may be a focal enzyme whose inactivation may be related to each of the disorders. Glucose-6-phosphatase is the terminal key enzyme in the gluconeogenesis pathway leading to increased blood glucose. Inhibition thereof may explain both the alternate reduction of pyruvate with concommittent increased formation of lactic acid, and the increase in the pentose phosphate pathway leading to hyperuricemia (as also observed in von Gierke's disease).
Brecher
A S
AS
Department of Chemistry, Bowling Green State University, OH 43403, USA.
Lehti
M D
MD
D000079:Acetaldehyde / Q000494:pharmacology*; D000437:Alcoholism / Q000150:complications / Q000201:enzymology*; D000818:Animals; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005943:Gluconeogenesis; D005952:Glucose-6-Phosphatase / Q000037:antagonists & inhibitors*; D007003:Hypoglycemia / Q000209:etiology*; D019344:Lactic Acid / Q000097:blood*; D019289:Pyruvic Acid / Q000097:blood; D011817:Rabbits; D014527:Uric Acid / Q000097:blood*
D004791:Enzyme Inhibitors; D014527:Uric Acid; D019344:Lactic Acid; D019289:Pyruvic Acid; D005952:Glucose-6-Phosphatase; D000079:Acetaldehyde