Hepatic UDP-glucuronic acid regulation during acetaminophen biotransformation in rats

Acetaminophen (AA) glucuronidation is capacity limited in several species after administration of high doses and previous data indicate that this phenomenon is due probably to a decrease in the concentration of the reaction cosubstrate UDP-glucuronic acid in liver. The rate-limiting determinant in UDP-glucuronic acid synthesis during AA glucuronidation is not known. The objective of the present study was to determine whether UDP-glucuronic acid synthesis during AA biotransformation is restricted by the supply of UDP-glucose or is limited by UDP-glucose dehydrogenase activity. Adult male Sprague-Dawley rats were injected with 600 mg/kg i.p of AA and liver was obtained 30, 60, 120 and 240 min later for quantitation of UDP-glucose, glycogen and UDP-glucuronic acid. AA was found to decrease markedly UDP-glucuronic acid concentration in liver 30, 60 and 120 min after injection (28, 52 and 58% of control values, respectively). In contrast, hepatic UDP-glucose levels were not altered after 30 min, but were decreased to 55 and 68% of control values 60 and 120 min after AA administration. Glycogen concentrations were decreased at the 30-min time interval only (78% of control). Therefore, maximal depletion of UDP-glucuronic acid occurred when UDP-glucose levels were not affected. UDP-glucose dehydrogenase is subject to product inhibition by NADH and UDP-glucuronic acid and it is possible that NADH accumulates during rapid utilization of UDP-glucuronic acid. Consequently, the effects of AA on cytosolic NADH/NAD ratios in liver were examined by determining the lactate/pyruvate ratio.(ABSTRACT TRUNCATED AT 250 WORDS)