Role of UDPGA flux in acetaminophen clearance and hepatotoxicity.
Factors which determine the acetaminophen glucuronidation capacity in the male rat have been examined. Conditions previously shown to increase (streptozotocin diabetes) or decrease (a 24 h fast) the glucuronidation capacity in vivo did not alter the microsomal glucuronyl transferase activity, indicating that the amount of enzyme is not rate-limiting. Acetaminophen caused a rapid depletion of hepatic levels of the co-substrate, UDPGA; both the extent of depletion and the time required for recovery back to pre-drug levels were dependent on the dose of acetaminophen administered. The amount of UPDGA required for the glucuronidation of a therapeutic dose was nearly equal to the total content of UDPGA in the liver; after a toxic dose, the UDPGA demand was over 100-fold greater than the normal basal level. It is concluded that the glucuronidation capacity of the animals is determined by their capacity to synthesize UDPGA, which in turn is dependent on flux through the glucuronic acid pathway.
D000042:Absorption; D000082:Acetaminophen / Q000378:metabolism / Q000633:toxicity*; D000818:Animals; D003921:Diabetes Mellitus, Experimental; D004305:Dose-Response Relationship, Drug; D005215:Fasting; D005965:Glucuronates / Q000378:metabolism; D014453:Glucuronosyltransferase / Q000378:metabolism; D007700:Kinetics; D008099:Liver / Q000187:drug effects* / Q000378:metabolism; D008297:Male; D051381:Rats; D014535:Uridine Diphosphate Glucuronic Acid / Q000378:metabolism*; D014539:Uridine Diphosphate Sugars / Q000378:metabolism*
D005965:Glucuronates; D014539:Uridine Diphosphate Sugars; D014535:Uridine Diphosphate Glucuronic Acid; D000082:Acetaminophen; D014453:Glucuronosyltransferase