Mechanism of Fasting-Induced Suppression of Acetaminophen Glucuronidation in the Rat

  • Veronica F. Price
  • Jennifer M. Schulte
  • Stephen M. Spaethe
  • David J. Jollow
Part of the Advances in Experimental Medicine and Biology book series (AEMB, volume 197)


Acetaminophen overdosage, taken either as a suicidal gesture or as an accidental poisoning, is a significant clinical entity and one that appears to be growing in incidence. Results from a recent study have shown that the percentage of total drug-related deaths associated with acetaminophen in England and Wales rose dramatically from 3.8% in 1973 to 21% in 1980; further, the number of acetaminophen-associated deaths was the highest of all drug-related deaths for the years 1978 to 1980 (1). Thus there is a need to define more clearly the reasons for differences in patient responsiveness and to develop new treatment regimens to decrease the severity of liver failure.


Blood Glucose Level Reactive Metabolite Glycogen Level Glycogen Deposition Increase Blood Glucose Level 
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  1. 1.
    M.D. Osselton, R.C. Blackmore, L.A. King and A.C. Moffat, Poisoning-associated deaths for England and Wales between 1973 and 1980, Human Toxicol. 3: 201 (1984).CrossRefGoogle Scholar
  2. 2.
    R.A. Flood and C.P. Seager, A retrospective examination of psychiatric case records. of patients who subsequently committed suicide, Brit. J. Psychiat. 114: 443 (1968).PubMedCrossRefGoogle Scholar
  3. 3.
    B. Barraclough, J. Bunch, B. Nelson and P. Sainsbury, A hundred cases of suicide: Clinical aspects, Brit. J. Psychiat. 125: 355 (1974).PubMedCrossRefGoogle Scholar
  4. 4.
    D. Pessayre, A. Dolder, J.-Y. Artigou, J.-C. Wandscheer, V. Descatoire, C. Degott and J.-P. Benhamou, Effect of fasting on metabolite-mediated hepatotoxicity in the rat, Gastroenterology, 77: 264 (1979).PubMedGoogle Scholar
  5. 5.
    A. Wendel, S. Feuerstein and K.-H. Konz, Acute paracetamol intoxication of starved mice leads to lipid peroxidation in vivo, Biochem. Pharmacol. 28: 2051 (1979).PubMedCrossRefGoogle Scholar
  6. 6.
    Strubett, E. Dost-Kempf, C.-P. Seigers, M. Younes, M. Volpel, U. Preuss and J.G. Dreckmann, The inlfuence of fasting on the susceptibility of mice to hepatotoxic injury, Tox. Appl. Pharmacol. 60: 66 (1981).CrossRefGoogle Scholar
  7. 7.
    R.M. Walker, T.E. Massey, T.F. McElligott and W.J. Racz, Acetaminophen toxicity in fed and fasted mice, Can. J. Physiol. Pharmacol. 60: 399 (1982).PubMedCrossRefGoogle Scholar
  8. 8.
    L.F. Prescott, N. Wright, P. Roscoe and S.S. Brown, Plasma-paracetamol half-life and hepatic necrosis in patients with paracetamol overdosage. Lancet, 1: 519 (1971).PubMedCrossRefGoogle Scholar
  9. 9.
    L.F. Prescott, Kinetics and metabolism of paracetamol and phenacetin, Brit. J. Pharmacol. 10: 291S (1980).Google Scholar
  10. 10.
    D.J. Jollow, S.S. Thorgeírsson, W.Z. Potter, M. Hashimoto and J.R. Mitchell, Acetaminophen-induced hepatic necrosis. VI. Metabolic disposition of toxic and nontoxic doses of acetaminophen, Pharmacology, 12: 251 (1974).PubMedCrossRefGoogle Scholar
  11. 11.
    D.J. Jollow, S. Roberts, V. Price and C. Smith, Biochemical basis for dose response relationships in reactive metabolite toxicity, in “Biological Reactive Intermediates II: Chemical Mechanisms and Biological Effects”, R. Snyder, D. V. Parke, J.J. Kocsis, G. Gibson amd D.J. Jollow, ed., Plenum Press, New York (1982).Google Scholar
  12. 12.
    V.F. Price and D.J. Jollow, Increased resistance of diabetic rats to acetaminophen-induced hepatotoxicity, J. Pharmacol. Exp. Ther. 220: 504 (1982).PubMedGoogle Scholar
  13. 13.
    C. Smith, and D.J. Jollow, Potentiation of acetaminophen induced liver necrosis in hamsters by galactosamine, Pharmacologist 18: 156 (1976).Google Scholar
  14. 14.
    V.F. Price and D.J. Jollow, Acetaminophen hepatotoxicity: Reduced susceptibility of diabetic rats, Pharmacologist 22: 245 (1980).Google Scholar
  15. 15.
    V.F. Price and D.J. Jollow, Role of UDPGA flux in acetaminophen clearance and hepatotoxicíty, Xenobiotica 7: 553 (1984).CrossRefGoogle Scholar
  16. 16.
    N.V. Carroll, R.W. Longley and J.H. Roe, The determination of glycogen in liver and muscle by the use of anthrone reagents, J. Biol. Chem. 220: 583 (1956).PubMedGoogle Scholar
  17. 17.
    R.G. Thurman and F.C. Kauffman, Factors regulating drug metabolism in intact hepatocytes, Pharmacol. Rev. 31: 229 (1980).Google Scholar
  18. 18.
    M. Sochor, N.Z. Baquer, and P. McLean, Glucose overutilization in diabetes: Evidence from studies on the changes in hexokinase, the pentose phosphate pathway and glucuronate-xylulose pathway in rat kidney cortex in diabetes, Arch. Bíochem. Biophys. 198: 632 (1979).PubMedCrossRefGoogle Scholar
  19. 19.
    S. Hizukuri and J. Larner, Studied on UDPG: m-1,4-glucan a-4-glucosyltransferase. VII. Conversion of the enzyme from glucose-6-phosphatedependent to independent form in liver, Biochemistry 3: 1783 (1964).PubMedCrossRefGoogle Scholar
  20. 20.
    H.G. Hers, The control of glycogen metabolism in the liver, Ann. Rev. Biochem. 45: 167 (1976).PubMedCrossRefGoogle Scholar
  21. 21.
    J. Zalitis and D.S. Feingold, The mechanism of action of UDPG dehydrogenase, Biochem. Biophys. Res. Commun. 31: 693 (1968)PubMedCrossRefGoogle Scholar
  22. 22.
    P. Moldeus, B. Anderson and A. Norling, Interaction of ethanol oxidation with glucuronidation in isolated hepatocytes, Biochem. Pharmacol. 27: 2583 (1978).PubMedCrossRefGoogle Scholar
  23. 23.
    A.I. Winegrad and C.L. Burden, Hyperactivity of the glucuronic acid pathway in diabetes mellitus. Trans. Assoc. Am. Physicians 75: 158 (1965).Google Scholar
  24. 24.
    A.I. Winegrad and C.L. Burden, L-Xylulose metabolism in diabetes mellitus, New England J. Med. 274: 298 (1966).CrossRefGoogle Scholar
  25. 25.
    J.W. Anderson, Alterations in the metabolic fate of glucose in the liver of diabetic animals, Am. J. Clin. Nutr. 27: 746 (1974).PubMedGoogle Scholar
  26. 26.
    J.W. Anderson, Metabolic abnormalities contributing to diabetic complications. I. Glucose metabolism in insulin-insensitive pathways, Am. J. Clin. Nutr. 28: 273 (1975).PubMedGoogle Scholar
  27. 27.
    Y. Hinolara, S. Takanashi, R. Nagashima and A. Shioya, Glucuronic acid pathway in alloxan diabetic rabbits. I. Urinary excretion of metabolite related to the glucuronic acid pathway. Jpn. J. Pharmacol. 24: 869 (1974).CrossRefGoogle Scholar
  28. 28.
    D.R.P. Tulsiani and O. Touster, Studies on dehydrogenases of the glucuronate-xylulose cycle in the livers of diabetic mice and rats, Diabetes 28: 793 (1979).PubMedCrossRefGoogle Scholar
  29. 29.
    V.F. Price, M.G. Miller and D.J. Jollow, Mechanism of fasting-induced potentiation of acetaminophen hepatotoxicity in the rat, Biochem. Pharmacol. Submitted.Google Scholar
  30. 30.
    V.F. Price and D.J. Jollow, Mechanism of fasting-induced suppression of acetaminophen glucuronidation in the rat, Biochem. Pharmacol. Submitted.Google Scholar
  31. 31.
    H.A. Krebs, The redox state of nicatinamide adenine dinucleotides in the cytoplasma and mitochondria of rat liver, Adv. Enzyme Res. 5: 409 (1967).CrossRefGoogle Scholar
  32. 32.
    J.R. Mitchell, D.J. Jollow, W.Z. Potter, D.C. Davis, J.R. Gillette and B.B. Brodie, Acetaminophen-induced hepatic necrosis. I. Role of drug metabolism, J. Pharmacol Exp. Ther. 187: 185 (1973).PubMedGoogle Scholar
  33. 33.
    M.F. Dixson, B. Dixson, S.R. Aparicio and D.P. Loney, Experimental paracetamol-induced hepatic necrosis: A light-and electron-microscope, and histochemical study, J. Path. 116: 17 (1975).CrossRefGoogle Scholar
  34. 34.
    J.A. Hinson, J.B. Mays and A.M. Cameron, Acetaminophen-induced hepatic glycogen depletion and hyperglycemia in mice, Biochem. Pharmacol. 32: 1979 (1983).PubMedCrossRefGoogle Scholar
  35. 35.
    J.A. Hinson, H. Han-Hsue, J.B. Mays, S.J. Holt, P. McLean and B. Ketterer, Acetaminophen-induced alterations in blood glucose and blood insulin levels in mice, Res. Commun. Chem. Path. Pharmacol. 43: 381 (1984).Google Scholar
  36. 36.
    V.F. Price and D.J. Jollow, Acute glucose does not reverse fasting-induced suppression of acetaminophen glucuronidation in the rat. Biochem. Pharmacol. Submitted.Google Scholar

Copyright information

© Plenum Press, New York 1986

Authors and Affiliations

  • Veronica F. Price
    • 1
  • Jennifer M. Schulte
    • 1
  • Stephen M. Spaethe
    • 1
  • David J. Jollow
    • 1
  1. 1.Department of PharmacologyMedical University of South CarolinaCharlestonUSA

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