Abstract
Acetaminophen (N-acetyl-p-aminophenol, APAP) toxicity is dependent upon APAP activation by cytochrome P450 to a metabolite which binds covalently to macromolecules as cellular glutathione becomes depleted (Potter, et al., 1973; Mitchell, et al., 1973; Jollow, et al., 1973; Dahlin, et al., 1984). Studies with an affinity purified anti-APAP antibody have demonstrated that, in mice, the covalent binding is not random, but is highly selective, and that binding to cytosolic protein(s) of approximately 58kD was most closely associated with APAP toxicity (Bartolone, et al., 1987; 1988; 1989a; Birge, et al., 1988; 1989; Beierschmitt, et al., 1989). While human liver has been demonstrated to activate APAP in vitro (Dybing, 1977), covalent binding has not been demonstrated during human APAP poisoning. The present study demonstrates for the first time that a similar, selective arylation of proteins also occurs in humans during APAP hepatotoxicity.
Access this chapter
Tax calculation will be finalised at checkout
Purchases are for personal use only
Preview
Unable to display preview. Download preview PDF.
Similar content being viewed by others
References
Bartolone, J.B., Sparks, K., Cohen, S.D. and Khairallah, E.A. (1987). Immunochemical detection of acetaminophen bound liver proteins. Biochem. Pharmacol. 36, 1193–1196.
Bartolone, J.B., Birge, R.B., Sparks, K., Cohen, S.D. and Khairallah, E.A. (1988). Immunochemical analysis of acetaminophen covalent binding to proteins: Partial characterization of the major acetaminophen-binding liver proteins. Biochem. Pharmacol. 37, 4763–4774.
Bartolone, J.B., Beierschmitt, W.P., Birge, R.B., Emeigh Hart, S.G., Wyand, S., Cohen, S.D. and Khairallah, E.A. (1989a). Selective acetaminophen metabolite binding to extrahepatic proteins: An in vivo and in vitro analysis. Toxicol. Appl. Pharmacol. 99, 240–249.
Bartolone, J.B., Cohen, S.D., and Khairallah, E.A. (1989b). Immunochemical localization of acetaminophen-bound liver proteins. Fund. Applied. Toxicol. 13, 859–862.
Beierschmitt, W.P., Brady, J.T., Bartolone, J.B., Wyand, D.S., Khairallah, E.A. and Cohen, S.D. (1989). Selective protein arylation and the age-dependency of acetaminophen hepatotoxicity in mice. Toxicol. Appl. Pharmacol. 98, 517–529.
Birge, R.B., Bartolone, J.B., Nishanian, E.V., Bruno, M.K., Mangold, J.B., Cohen, S.D. and Khairallah, E.A. (1988). Dissociation of covalent binding from the oxidative effects of acetaminophen: studies using dimethylated acetaminophen derivatives. Biochem. Pharmacol. 37, 3383–3393.
Birge, R.B., Bartolone, J.B., McCann, D.J., Mangold, J.B., Cohen, S.D. and Khairallah, E.A. (1989). Selective protein arylation by acetaminophen and 2,6-dimethyl-acetaminophen in cultured hepatocytes from phenobarbital-induced and uninduced mice. Biochem. Pharmacol. 38, 4429–4438.
Dahlin, D.C., Miwa, G.T., Lu, A.Y.H. and Nelson, S.D. (1984). N-acetyl-p-benzoquinone imine: a cytochrome P-450-mediated oxidation product of acetaminophen. Proc. Nat. Acad. ScI. 81, 1327–1331.
Dybing, E. (1977). Activation of a-methyldopa, paracetamol and furosemide by human liver microsomes. Acta Pharmacol. et toxicol. 41, 89–93.
Gonzalez, F.J. (1988). The molecular biology of the cytochrome P-450s. Pharmacol. Rev. 40, 243–288.
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, 185–194.
Laemmli, U.K. (1970). Cleavage of structural proteins during the assembly of the head bacteriophage T4. Nature (London) 227, 680–685.
Lowry, O.H., Rosebrough, N.J., Farr, A.L. and Randall, R.J. (1951). Protein measurement with the Folin phenol reagent. J. Biol. Chem. 193, 265–275.
Mitchell, J.R., Jollow D.J., Potter, W.Z., Davis, D.C., Gillette, J.R. and Brodie, B.B. (1973). Acetaminophen-induced hepatic necrosis. I. Role of drug metabolism. J. Pharmacol. Exp. Therap. 187, 185–194.
Placke, M.E., Ginsberg, G.L., Wyand, D.S. and Cohen, S.D. (1987). Ultrastructural and biochemical changes during acute acetaminophen-induced hepatotoxicity in the mouse. A time and dose study. Toxicologic Pathol. 15, 431–438.
Potter W.Z., Davis D.C., Mitchell J.R., Jollow, D.J., Gillette, J.R. and Brodie, B.B. (1973). Acetaminophen-induced hepatic necrosis. III. Cytochrome-P450 mediated covalent binding in vitro. J. Pharmacol. Exp. Ther. 187, 203–210.
Roberts, D.W., Hinson, J.A., Benson, R.W., Pumford, N.R., Warbritton, A.R., Crowell, J.A. and Bucci, T.J. (1989). Immunohistochemical localization of 3-(cystein-S-y1) acetaminophen protein adducts in livers of mice treated with acetaminophen. The Toxicologist. 9, 47.
Author information
Authors and Affiliations
Editor information
Editors and Affiliations
Rights and permissions
Copyright information
© 1991 Plenum Press, New York
About this chapter
Cite this chapter
Birge, R.B., Bartolone, J.B., Tyson, C.A., Hart, S.G.E., Cohen, S.D., Khairallah, E.A. (1991). Selective Binding of Acetaminophen (APAP) to Liver Proteins in Mice and Men. In: Witmer, C.M., Snyder, R.R., Jollow, D.J., Kalf, G.F., Kocsis, J.J., Sipes, I.G. (eds) Biological Reactive Intermediates IV. Advances in Experimental Medicine and Biology, vol 283. Springer, Boston, MA. https://doi.org/10.1007/978-1-4684-5877-0_87
Download citation
DOI: https://doi.org/10.1007/978-1-4684-5877-0_87
Publisher Name: Springer, Boston, MA
Print ISBN: 978-1-4684-5879-4
Online ISBN: 978-1-4684-5877-0
eBook Packages: Springer Book Archive