Effect of glucose and gluconeogenic substrates on fasting-induced suppression of acetaminophen glucuronidation in the rat.
Previous studies in rats have shown that an acute fast decreases the apparent rate constant for glucuronidation of hepatotoxic doses of acetaminophen which results in a prolongation of the mean residence time of the drug in the animals and, hence, increased acetaminophen reactive metabolite formation and liver injury. Since acetaminophen glucuronidation under these conditions is limited by UDPGA formation, we have attempted to reverse the potentiating effects of fasting by administering glucose or gluconeogenic substrates. Histological and pharmacokinetic studies revealed that glucose (2 g/kg, i.p.) given 0.25 and 1.5 hr after acetaminophen (700 mg/kg, i.p.) did not protect the rats from liver injury or enhance acetaminophen glucuronidation. The administered glucose did not increase hepatic levels of UDP-glucose or UDPGA either basally or following administration of a hepatotoxic dose of acetaminophen. Administration of the gluconeogenic substrates, lactate, alanine, fructose and galactose, raised blood glucose levels, but did not protect the rats from liver injury or enhance glucuronidation, suggesting that the glucose-6-phosphate formed from these compounds was not available for UDPGA production for acetaminophen glucuronidation. Collectively, these studies indicate that administration of glucose and these gluconeogenic substrates does not reverse the fasting-induced potentiation of acetaminophen hepatotoxicity, and that the rate-determining step for UDPGA synthesis for glucuronidation of hepatotoxic doses of acetaminophen is prior to UDP-glucose formation.
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Department of Cell and Molecular Pharmacology and Experimental Therapeutics, Medical University of South Carolina, Charleston 29425.
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D000082:Acetaminophen / Q000378:metabolism* / Q000493:pharmacokinetics / Q000633:toxicity; D000409:Alanine / Q000494:pharmacology; D000818:Animals; D001711:Biotransformation; D001786:Blood Glucose / Q000378:metabolism; D056486:Chemical and Drug Induced Liver Injury / Q000209:etiology*; D005215:Fasting; D005632:Fructose / Q000494:pharmacology; D005690:Galactose / Q000494:pharmacology; D005943:Gluconeogenesis; D005947:Glucose / Q000494:pharmacology*; D005965:Glucuronates / Q000378:metabolism; D020723:Glucuronic Acid; D007773:Lactates / Q000494:pharmacology; D008112:Liver Glycogen / Q000378:metabolism; D008297:Male; D051381:Rats; D014532:Uridine Diphosphate Glucose / Q000378:metabolism; D014535:Uridine Diphosphate Glucuronic Acid / Q000378:metabolism
D001786:Blood Glucose; D005965:Glucuronates; D007773:Lactates; D008112:Liver Glycogen; D014535:Uridine Diphosphate Glucuronic Acid; D005632:Fructose; D000082:Acetaminophen; D020723:Glucuronic Acid; D005947:Glucose; D000409:Alanine; D014532:Uridine Diphosphate Glucose; D005690:Galactose