Intracellular inhibition of UDP-glucose dehydrogenase during ethanol oxidation.

The enzymatic basis for inhibition of drug glucuronidation during ethanol oxidation was investigated in isolated rat hepatocytes. The intracellular rate of glucuronidation was varied independently by controlling the steady-state O2 concentration and the concentrations of UDP-glucose and UDP-glucuronic acid were measured in the absence and presence of 20 mM ethanol. Ethanol caused substantial inhibition of the glucuronidation rate which corresponded to a significant decrease in UDP-glucuronic acid concentration but not in UDP-glucose concentration. A plot of glucuronidation rate as a function of cellular UDP-glucuronic acid concentration yielded a single curve for incubations with or without ethanol; a similar plot of glucuronidation against UDP-glucose concentration gave separate curves for the two incubation conditions. These results clearly define the UDP-glucose dehydrogenase reaction as the site of inhibition during ethanol oxidation.