Kinetics of ethanol inhibition of galactose elimination in perfused pig liver.
The effect of ethanol (5--25 mM) on the galactose elimination kinetics in the intact liver was studied in the isolated perfused pig liver, using the steady-state infusion technique. Ethanol reduced galactose-Vmax on average to 0.07 mmol/min kg liver in six experiments from 0.43 mmol/min kg obtained in control experiments without ethanol. Also Km was significantly reduced from 0.23 mmol/l plasma water to 0.03 mmol/l. Ethanol increased UDP-galactose ten-fold simultaneous with a rise in hepatic outflow ratio of lactate to pyruvate to about 300 from 10; this indicates that ethanol inhibits epimerase. In experiments with increasing galactose elimination rates, the concentration of galactose-1-P increased much less than the concentration of galactose, and the phosphorylation of galactose therefore seems to be rate-limiting. In vitro galactokinase is inhibited by galactose-1-P. In the present study ethanol increased galactose-1-P five to ten times, and the reduction of Vmax and Km by ethanol could be explained by uncompetitive inhibition by galactose-1-P with Ki about 0.1 mmol/l. Ethanol decreased UDP-glucose to about 40% and UTP to less than 5%, probably due to trapping as UDP-galactose. This may depress the forward transferase reaction, and therefore the other co-substrate galactose-1-P rises--and inhibits galactokinase.
D000244:Adenosine Diphosphate / Q000378:metabolism; D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D002462:Cell Membrane / Q000378:metabolism; D000431:Ethanol / Q000378:metabolism / Q000494:pharmacology*; D005260:Female; D005690:Galactose / Q000037:antagonists & inhibitors* / Q000378:metabolism; D005695:Galactosephosphates / Q000378:metabolism; D007700:Kinetics; D007773:Lactates / Q000378:metabolism; D008099:Liver / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D010477:Perfusion; D011773:Pyruvates / Q000378:metabolism; D019998:Racemases and Epimerases / Q000378:metabolism; D013552:Swine; D014532:Uridine Diphosphate Glucose / Q000378:metabolism
D005695:Galactosephosphates; D007773:Lactates; D011773:Pyruvates; D000431:Ethanol; D000244:Adenosine Diphosphate; D000255:Adenosine Triphosphate; D019998:Racemases and Epimerases; D014532:Uridine Diphosphate Glucose; D005690:Galactose