Inhibition of rat liver transaminases by low levels of acetaldehyde and the pharmacologic effects of B6 vitamers.
To better define the significance and mechanism of acetaldehyde-mediated transaminase inhibition, acetaldehyde metabolism was studied in rat liver homogenates and cytosols. When either preparation was incubated at 37 degrees with 1.5 mM acetaldehyde for 4 hr, acetaldehyde levels fell rapidly in the first 30 min and little inhibition of aspartate aminotransferase (GOT) or alanine aminotransferase (GPT) resulted. In contrast, incubation with 50 mM ethanol also resulted in a peak acetaldehyde level of 1.0 to 1.5 mM by 2 hr, but this level was then maintained for the next 2 hr and transaminases were inhibited by 20-35%. Sequential addition of low dose (125-250 microM) pulses of acetaldehyde to rat liver preparations resulted in a progressive decrease in the rate of acetaldehyde disappearance. When the pulsing schedule was adjusted accordingly to maintain acetaldehyde levels between 50 and 250 microM for 8 hr, transaminases were again inhibited by 20-40%. Finally, addition of 1-5 mM pyridoxal and pyridoxal 5'-phosphate, aldehydic B6 vitamers, to cytosols 2-4 hr after pulsing with acetaldehyde was begun, almost completely prevented further transaminase inhibition. In contrast, the non-aldehydic B6 vitamers, pyridoxine, pyridoxamine and pyridoxamine 5'-phosphate, did not affect acetaldehyde-mediated transaminase inhibition. These findings suggest that (1) prolonged exposure to low levels of acetaldehyde impairs acetaldehyde metabolism in rat liver homogenates and cytosols; (2) acetaldehyde toxicity may be more dependent on sustained exposure to acetaldehyde than on the peak level of acetaldehyde attained; and (3) aldehydic B6 vitamers can modify on-going acetaldehyde-mediated transaminase inhibition.
Crouch
J Y
JY
Veterans Administration Medical Center, West Haven, CT 06516.
Solomon
L R
LR
D000079:Acetaldehyde / Q000378:metabolism / Q000494:pharmacology*; D000410:Alanine Transaminase / Q000037:antagonists & inhibitors*; D000818:Animals; D001219:Aspartate Aminotransferases / Q000037:antagonists & inhibitors*; D008099:Liver / Q000201:enzymology*; D011736:Pyridoxine / Q000494:pharmacology*; D051381:Rats; D011919:Rats, Inbred Strains
D001219:Aspartate Aminotransferases; D000410:Alanine Transaminase; D000079:Acetaldehyde; D011736:Pyridoxine