Mechanism of fasting-induced suppression of acetaminophen glucuronidation in the rat.
These studies have revealed the occurrence of important relationships among nutritional status, hepatic intermediary metabolism, acetaminophen glucuronidation and susceptibility to hepatotoxicity. During an acute fast hepatic metabolism of glucose is altered profoundly. The altered metabolic poise of the fasted liver appears to favor higher G6P'-ase activity relative to UDPG pyrophosphorylase activity, resulting in decreased production of UDPG secondary to depleted glycogen levels. Although the rate of gluconeogenesis is enhanced and maintains UDPG levels at approximately 60% of those in fed animals, the decreased production of UDPG limits the rate of UDPGA synthesis for glucuronidation of high doses of acetaminophen. Since glucuronidation is the major pathway of clearance of these high doses of the drug, UDPG synthesis is rate-limiting for acetaminophen elimination; the resulting prolongation of the drug half-life is associated with increased amount of reactive metabolite formed and potentiation of liver injury. Glucuronidation is also the major pathway of clearance in the human overdose situation and if UDPG production occupies a similar rate-determining role, then enhancement of UDPG production might be of significant value in the therapy of acetaminophen overdosage. Thus, determination of factors which control UDPG production in the liver under different physiological (nutritional/hormonal) conditions has both fundamental and practical value.
D000082:Acetaminophen / Q000378:metabolism*; D000818:Animals; D001786:Blood Glucose / Q000378:metabolism; D005215:Fasting; D005947:Glucose / Q000378:metabolism; D005965:Glucuronates / Q000378:metabolism*; D007700:Kinetics; D008099:Liver / Q000378:metabolism; D008112:Liver Glycogen / Q000378:metabolism; D051381:Rats; D014532:Uridine Diphosphate Glucose / Q000378:metabolism; D014535:Uridine Diphosphate Glucuronic Acid / Q000378:metabolism*; D014539:Uridine Diphosphate Sugars / Q000378:metabolism*; D014996:Xylulose / Q000378:metabolism
D001786:Blood Glucose; D005965:Glucuronates; D008112:Liver Glycogen; D014539:Uridine Diphosphate Sugars; D014535:Uridine Diphosphate Glucuronic Acid; D000082:Acetaminophen; D014996:Xylulose; D005947:Glucose; D014532:Uridine Diphosphate Glucose