Mechanism of decreased acetaminophen glucuronidation in the fasted rat.
The mechanism by which an acute fast decreases the glucuronidation of hepatotoxic doses of acetaminophen in the rat was examined. Fasting did not depress the level of the enzyme, glucuronyl transferase, or the basal level of the co-substrate, UDP-glucuronic acid (UDPGA). Administration of a hepatotoxic dose of acetaminophen rapidly depleted UDPGA levels in both fed and fasted rats to the same nadir. Fed and fasted rats differed in that the rate of repletion of UDPGA levels was markedly slower in fasted rats. The total hepatic levels of UDP-glucose dehydrogenase and its cofactor, NAD+, were not decreased by fasting. In fasted rats, hepatic levels of the UDPGA precursor, UDP-glucose, were approximately 60% those of fed rats both before and after a hepatotoxic dose of acetaminophen. In fed rats, acetaminophen induced a marked depletion of hepatic glycogen levels and a dramatic increase in blood glucose levels. Acetaminophen induced a similar marked increase in blood glucose levels in fasted rats in spite of the fact that they lacked hepatic glycogen. It is concluded that the fasting-induced decrease in the glucuronidation of hepatotoxic doses of acetaminophen results from decreased production of UDPGA. The decreased synthetic capacity for UDPGA does not appear to be due to the inability of the liver to produce glucose units per se, but rather to the fasting-induced altered activities of the enzymes of carbohydrate metabolism which, in turn, alter the fate of glucose-6-phosphate derived from gluconeogenesis.
D000082:Acetaminophen / Q000031:analogs & derivatives* / Q000378:metabolism; D000818:Animals; D001786:Blood Glucose / Q000032:analysis; D005215:Fasting; D014453:Glucuronosyltransferase / Q000032:analysis; D008099:Liver / Q000378:metabolism; D008112:Liver Glycogen / Q000032:analysis; D008297:Male; D009243:NAD / Q000032:analysis; D051381:Rats; D014532:Uridine Diphosphate Glucose / Q000032:analysis; D014533:Uridine Diphosphate Glucose Dehydrogenase / Q000032:analysis; D014535:Uridine Diphosphate Glucuronic Acid / Q000032:analysis / Q000096:biosynthesis
D001786:Blood Glucose; D008112:Liver Glycogen; D009243:NAD; D014535:Uridine Diphosphate Glucuronic Acid; D000082:Acetaminophen; C037386:acetaminophen glucuronide; D014533:Uridine Diphosphate Glucose Dehydrogenase; D014453:Glucuronosyltransferase; D014532:Uridine Diphosphate Glucose