Acetaminophen decreases adenosine 3'-phosphate 5'-phosphosulfate and uridine diphosphoglucuronic acid in rat liver.
The purpose of this investigation was to determine the effects of acute administration of acetaminophen on adenosine 3'-phosphate 5'-phosphosulfate (PAPS) and UDP-glucuronic acid concentrations in fed male rats. Acetaminophen produced a dosage-dependent decline in rat hepatic PAPS concentrations which was significant after dosages of 150, 300, or 600 mg/kg, ip. The time course of the decline in PAPS values after 600 mg acetaminophen/kg showed that PAPS concentrations reached a nadir 1 hr after dosing (40% of control values). Serum sulfate concentrations were also decreased by large dosages of acetaminophen (32 and 15% of control 2 hr after 150 and 600 mg/kg, respectively) and a significant, positive correlation between serum sulfate and hepatic PAPS concentrations was noted. In addition, hepatic cysteine and glutathione concentrations were lowered by high dosages of acetaminophen. Hepatic UDP-glucuronic acid concentrations were greatly decreased for 2 hr after a dosage of 600 mg acetaminophen/kg (15, 23, and 42% of control 0.5, 1.0, and 2.0 hr after dosing, respectively) whereas 150 mg/kg produced a less pronounced and more transient decrease. These findings demonstrate that both PAPS and UDP-glucuronic acid concentrations in liver are decreased after administration of acetaminophen and imply that capacity-limited sulfation and glucuronidation of acetaminophen are due to a decrease in co-substrate availability.
Hjelle
J J
JJ
Hazelton
G A
GA
Klaassen
C D
CD
D000082:Acetaminophen / Q000494:pharmacology*; D000227:Adenine Nucleotides / Q000378:metabolism*; D000818:Animals; D003545:Cysteine / Q000378:metabolism; D003864:Depression, Chemical; D005978:Glutathione / Q000378:metabolism; D008099:Liver / Q000187:drug effects / Q000378:metabolism*; D008297:Male; D010724:Phosphoadenosine Phosphosulfate / Q000378:metabolism*; D051381:Rats; D011919:Rats, Inbred Strains; D013431:Sulfates / Q000097:blood; D013997:Time Factors; D014535:Uridine Diphosphate Glucuronic Acid / Q000378:metabolism*; D014539:Uridine Diphosphate Sugars / Q000378:metabolism*
D000227:Adenine Nucleotides; D013431:Sulfates; D014539:Uridine Diphosphate Sugars; D014535:Uridine Diphosphate Glucuronic Acid; D000082:Acetaminophen; D010724:Phosphoadenosine Phosphosulfate; D005978:Glutathione; D003545:Cysteine