Effect of Diethyl Ether on the Bioactivation, Detoxification, and Hepatotoxicity of Acetaminophen in Vitro and in Vivo

  • Peter G. Wells
  • Esther C. A. To
Part of the Advances in Experimental Medicine and Biology book series (AEMB, volume 197)


Diethyl ether (ether) is used widely as a general anesthetic in animal research, and it remains a convenient human anesthetic in some third world countries. Acetaminophen (N-acetyl-p-aminophenol, APAP, Tylenol®) is a widely used analgesic/antipyretic drug which in high doses can cause centrilobular hepatic necrosis in animals (Boyd and Bereczky, 1966) and humans (Proudfoot and Wright, 1970). Hepatotoxicity is thought to result from cytochromes P-450-catalysed bioactivation of a small amount of acetaminophen to a toxic, reactive intermediary metabolite (Mitchell et al., 1973a), while up to 60% of acetaminophen is eliminated by a competing glucuronidation pathway (fig. 1). Under normal conditions, the reactive intermediate is evanescent, being immediately detoxified by enzymatic conjugation with hepatic reduced glutathione (GSH) and subsequently excreted as cysteine and N-acetylcysteine conjugates (Mitchell et al., 1973b). However, if the amount of acetaminophen bioactivated is increased, or if detoxification of the reactive intermediate is reduced, then the available reactive intermediate arylates hepatic macromolecules, which is thought to initiate processes leading to hepatocellular necrosis (Mitchell et al., 1973a; Jollow et al., 1973).


Covalent Binding Cysteine Conjugate Glucuronyl Transferase Acetaminophen Glucuronide Acetaminophen Concentration 
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  1. Booth, J., Boyland, E. and Sims, P. (1961) An enzyme from rat liver catalysing conjugations with glutathione. Biochem. J. 79: 516–524.PubMedGoogle Scholar
  2. Boyd, E.M. and Bereczky, G.M. (1966) Liver necrosis from paracetamol. Br. J. Pharmacol. 26: 606–614.Google Scholar
  3. Eriksson, G. and Strath, D. (1981) Decreased UDP-glucuronic acid in rat liver after ether narcosis. FEBS Lett. 124: 39–42.PubMedCrossRefGoogle Scholar
  4. Habig, W.H., Pabst, M.J. and Jakoby, W.B. (1974) Glutathione S-transferases. J. Biol. Chem. 249: 7130–7139.PubMedGoogle Scholar
  5. Imai, Y., Ito, A., and Sato, N. (1966) Evidence for biochemically different types of vesicles in the hepatic microsomal fraction. J. Biochem. 60: 417–428.PubMedGoogle Scholar
  6. Johannessen, W., Gadeholt, G. and Aarbakke, J. (1981) Effects of diethyl ether anaesthesia on the pharmacokinetics of antipyrine and paracetamol in the rat. J. Pharm. Pharmacol. 33: 365–368.PubMedCrossRefGoogle Scholar
  7. Jollow, D.J., Mitchell, J.R., Potter, W.Z., Davis, D.C., Gillette, J.R. and Brodie, B.B. (1973) Acetaminophen-induced hepatic necrosis. II. Role of covalent binding in vivo. J. Pharmacol. Exp. Ther. 187: 195–201.PubMedGoogle Scholar
  8. Mitchell,J.R., Jollow, D.J. Potter, W.Z., Davis, D.C., Gillette, J.R. and Brodie, B.B. (1973a) Acetaminophen-induced hepatic necrosis. L Role of drug metabolism. J. Pharmacol. Exp. Ther. 187: 185–194.PubMedGoogle Scholar
  9. Mitchell, J.R., Jollow, D.J., Potter, W.Z., Davis, D.C., Gillette, J.R. and Brodie, B.B. (1973b) Acetaminophen-induced hepatic necrosis. IV. Protective role of glutathione. J. Pharmacol. Exp. Ther. 187: 211–217.PubMedGoogle Scholar
  10. Omura, T. and Sato, R. (1964) The carbon monoxide pigment of liver microsomes. I. Evidence for its haemoprotein nature. J. Biol. Chem. 239: 2370–2385.PubMedGoogle Scholar
  11. Orrenius, S., Jewell, S.A., Bellomo, G., Thor, H., Jones, D.P. and Smith, M.T. (1983). Regulation of calcium compartmentation in the hepatocyte–a critical role of glutathione. In: Functions of Glutathione: Biochemical, Physiological, Toxicological and Clinical Aspects, A. Larsson, S. Orrenius, A. Holmgren and B. Mannervik (eds.), pp. 261–271, Raven Press, New York.Google Scholar
  12. Proudfoot, A.T. and Wright, N. (1970) Acute paracetamol poisoning. Br. Med. J. 3: 557–558.PubMedCrossRefGoogle Scholar
  13. Sedlak, J. and Lindsay, R.H. (1968) Estimation of total, protein-bound and nonprotein sulphydryl groups in tissues with Ellman’s reagent. Analyt. Biochem. 25: 192–205.PubMedCrossRefGoogle Scholar
  14. To, E.C.A. and Wells, P.G. (1984) Rapid and sensitive assays using high-performance liquid chromatography to measure the activities of phase II drug metabolising enzymes: glucuronyl transferase and sulfotransferase. J. Chromatogr. 301: 282–287.PubMedCrossRefGoogle Scholar
  15. To, E.C.A. and Wells, P.G. ( 1985, accepted). Repetitive microvolumetric sampling and analysis of acetaminophen and its toxicologically relevant metabolites in murine plasma and urine using high-performance liquid chromatography. J. Analyt. Toxicol.Google Scholar
  16. Umeda, T. and Inaba, T. (1978) Effects of anesthetics on diphenylhydantoin metabolism in the rat: possible inhibition by diethyl ether. Can. J. Physiol. Pharmacol. 56: 241–244.PubMedCrossRefGoogle Scholar
  17. Watkins, J.B. and Klaassen, C.D. (1982) Determination of hepatic uridine 5’-diphosphoglucuronic acid concentration with diethylstilbestrol. J. Pharmacol. Methods 7: 145–151.PubMedCrossRefGoogle Scholar
  18. Wells, P.G., Boerth, R.C., Oates, J.A. and Harbison, R.D. (1980) Toxicologic enhancement by a combination of drugs which deplete hepatic glutathione: acetaminophen and doxorubicin (Adriamycin®). Toxicol. Appl. Pharmacol. 54: 197–209.PubMedCrossRefGoogle Scholar
  19. Wells, P.G. and Ramji, P. (1983) Modulation of acetaminophen biotransformation and hepatotoxicity by diethyl ether. Proc. Can. Fed. Biol. Soc. 26: 228.Google Scholar
  20. Wells, P.G., Ramji, P. and Ku, M.S.W. ( 1985, accepted) Delayed enhancement of acetaminophen hepatotoxicity by general anesthesia using diethyl ether or halothane. Fundam. Appl. Toxicol.Google Scholar
  21. Wells, P.G. and To, E.C.A. (1985) Murine hepatotoxicity: dependence of individual peak plasma glutamic-pyruvic transaminase (GPT) concentrations on in vivo covalent binding of acetaminophen. Proc. Can. Fed. Biol. Soc. 28: 228.Google Scholar

Copyright information

© Plenum Press, New York 1986

Authors and Affiliations

  • Peter G. Wells
    • 1
  • Esther C. A. To
    • 1
  1. 1.Faculty of PharmacyUniversity of TorontoTorontoCanada

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