Kinetics of ethanol inhibition of galactose elimination in perfused pig liver

Abstract

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-V_max, 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 K_m 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 V_max and K_m by ethanol could be explained by uncompetitive inhibition by galactose-1-P with K₁, 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.