![[Feedback]](/icons/banner/feedbackACT.gif){kind=icon}
![[For Subscribers]](/icons/banner/subscriberACT.gif){kind=icon}
![[Archive]](/icons/banner/archiveACT.gif){kind=icon}
![[Search]](/icons/banner/searchACT.gif){kind=icon}
![[Contents]](/icons/banner/tocACT.gif){kind=icon}
|
|
|
|
|
||
1 Laboratory of Chemical Pharmacology, National Heart and Lung Institute, National Institutes of Health, Bethesda, Maryland
Doses of 3H-acetaminophen (300-750 mg/kg) that cause necrosis in mice were shown to result in large amounts of radiolabeled material covalently bound to mouse liver protein in vivo (2 nmol/mg of protein or approximately one molecule bound per two molecules of protein in microsomes and cytoplasm). Both covalent binding and hepatic necrosis were dose dependent, and the peak level of binding preceded the development of recognizable necrosis by at least one to two hours. Pretreatment of mice with phenobarbital, piperonyl butoxide or cobaltous chloride, which changed the rate of metabolism of 3H-acetaminophen and altered the severity of hepatic necrosis, similarly affected the extent of hepatic binding of radiolabeled metabolite. Furthermore, the degree of binding in individual mice was always directly proportional to the severity of hepatic necrosis regardless of the biologic variation among various animals. Accordingly, we propose that acetaminophen-induced hepatic necrosis may be caused by the covalent binding of a chemically reactive metabolite to vital hepatsic macromolecules.
Submitted on June 29, 1972
This article has been cited by other articles:
|
|
 |
|
  L. M. Aleksunes, S. N. Campion, M. J. Goedken, and J. E. Manautou Acquired Resistance to Acetaminophen Hepatotoxicity is Associated with Induction of Multidrug Resistance-Associated Protein 4 (Mrp4) in Proliferating Hepatocytes Toxicol. Sci., August 1, 2008; 104(2): 261 - 273. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 K. J. Heard Acetylcysteine for Acetaminophen Poisoning N. Engl. J. Med., July 17, 2008; 359(3): 285 - 292. [Full Text] [PDF]
|
|
|
|
 |
|
 P. J. Murphy The Development of Drug Metabolism Research as Expressed in the Publications of ASPET: Part 2, 1959-1983 Drug Metab. Dispos., June 1, 2008; 36(6): 981 - 985. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 N. Hanawa, M. Shinohara, B. Saberi, W. A. Gaarde, D. Han, and N. Kaplowitz Role of JNK Translocation to Mitochondria Leading to Inhibition of Mitochondria Bioenergetics in Acetaminophen-induced Liver Injury J. Biol. Chem., May 16, 2008; 283(20): 13565 - 13577. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. Yalcin, A Bilgili, I Onbasilar, G Eraslan, and M Ozdemir Synergistic action of sodium selenite and N-acetylcysteine in acetaminophen-induced liver damage Human and Experimental Toxicology, May 1, 2008; 27(5): 425 - 429. [Abstract] [PDF]
|
|
|
|
 |
|
 S. K. Ramaiah and H. Jaeschke Role of Neutrophils in the Pathogenesis of Acute Inflammatory Liver Injury Toxicol Pathol, October 1, 2007; 35(6): 757 - 766. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 L. P. James, J. A. Hinson, E. M. Alonso, L. S. Hynan, W. M. Lee, T. J. Davern, R. H. Squires, and and the Pediatric Acute Liver Failure Study Group Acetaminophen Protein Adducts in Children With Acute Liver Failure of Indeterminate Cause: In Reply Pediatrics, February 1, 2007; 119(2): 419 - 420. [Full Text] [PDF]
|
|
|
|
|
|
F. J. Gonzalez CYP2E1 Drug Metab. Dispos., January 1, 2007; 35(1): 1 - 8. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. V. Terneus, K. K. Kiningham, A. B. Carpenter, S. B. Sullivan, and M. A. Valentovic Comparison of S-Adenosyl-L-methionine and N-Acetylcysteine Protective Effects on Acetaminophen Hepatic Toxicity J. Pharmacol. Exp. Ther., January 1, 2007; 320(1): 99 - 107. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. H. Chang, C. J. Kochansky, and M. Shou The Role of P-glycoprotein in the Bioactivation of Raloxifene Drug Metab. Dispos., December 1, 2006; 34(12): 2073 - 2078. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
D. Botta, S. Shi, C. C. White, M. J. Dabrowski, C. L. Keener, S. L. Srinouanprachanh, F. M. Farin, C. B. Ware, W. C. Ladiges, R. H. Pierce, et al. Acetaminophen-induced Liver Injury Is Attenuated in Male Glutamate-cysteine Ligase Transgenic Mice J. Biol. Chem., September 29, 2006; 281(39): 28865 - 28875. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
L. P. James, E. M. Alonso, L. S. Hynan, J. A. Hinson, T. J. Davern, W. M. Lee, R. H. Squires, and the Pediatric Acute Liver Failure Study Group Detection of Acetaminophen Protein Adducts in Children With Acute Liver Failure of Indeterminate Cause Pediatrics, September 1, 2006; 118(3): e676 - e681. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
G. Dai, L. He, N. Chou, and Y.-J. Y. Wan Acetaminophen Metabolism Does Not Contribute to Gender Difference in Its Hepatotoxicity in Mouse Toxicol. Sci., July 1, 2006; 92(1): 33 - 41. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 H. C. Yohe, K. A. O'Hara, J. A. Hunt, T. J. Kitzmiller, S. G. Wood, J. L. Bement, W. J. Bement, J. G. Szakacs, S. A. Wrighton, J. M. Jacobs, et al. Involvement of Toll-like receptor 4 in acetaminophen hepatotoxicity Am J Physiol Gastrointest Liver Physiol, June 1, 2006; 290(6): G1269 - G1279. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
H. Jaeschke and M. L. Bajt Intracellular Signaling Mechanisms of Acetaminophen-Induced Liver Cell Death Toxicol. Sci., January 1, 2006; 89(1): 31 - 41. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 G. Dai, N. Chou, L. He, M. A. Gyamfi, A. J. Mendy, A. L. Slitt, C. D. Klaassen, and Y.-J. Y. Wan Retinoid X Receptor {alpha} Regulates the Expression of Glutathione S-transferase Genes and Modulates Acetaminophen-Glutathione Conjugation in Mouse Liver Mol. Pharmacol., December 1, 2005; 68(6): 1590 - 1596. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
C. Cover, P. Fickert, T. R. Knight, A. Fuchsbichler, A. Farhood, M. Trauner, and H. Jaeschke Pathophysiological Role of Poly(ADP-Ribose) Polymerase (PARP) Activation during Acetaminophen-Induced Liver Cell Necrosis in Mice Toxicol. Sci., March 1, 2005; 84(1): 201 - 208. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. Gu, H. Cui, M. Behr, L. Zhang, Q.-Y. Zhang, W. Yang, J. A. Hinson, and X. Ding In Vivo Mechanisms of Tissue-Selective Drug Toxicity: Effects of Liver-Specific Knockout of the NADPH-Cytochrome P450 Reductase Gene on Acetaminophen Toxicity in Kidney, Lung, and Nasal Mucosa Mol. Pharmacol., March 1, 2005; 67(3): 623 - 630. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 C. V. Srikanth, A. K. Chakraborti, and A. K. Bachhawat Acetaminophen toxicity and resistance in the yeast Saccharomyces cerevisiae Microbiology, January 1, 2005; 151(1): 99 - 111. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
Y. Ito, E. R. Abril, N. W. Bethea, and R. S. McCuskey Inhibition of Matrix Metalloproteinases Minimizes Hepatic Microvascular Injury in Response to Acetaminophen in Mice Toxicol. Sci., January 1, 2005; 83(1): 190 - 196. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
T. R. Knight, M. W. Fariss, A. Farhood, and H. Jaeschke Role of Lipid Peroxidation as a Mechanism of Liver Injury after Acetaminophen Overdose in Mice Toxicol. Sci., November 1, 2003; 76(1): 229 - 236. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. L. Bajt, T. R. Knight, A. Farhood, and H. Jaeschke Scavenging Peroxynitrite with Glutathione Promotes Regeneration and Enhances Survival during Acetaminophen-Induced Liver Injury in Mice J. Pharmacol. Exp. Ther., October 1, 2003; 307(1): 67 - 73. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
K. Shankar, V. S. Vaidya, U. M. Apte, J. E. Manautou, M. J. J. Ronis, T. J. Bucci, and H. M. Mehendale Type 1 Diabetic Mice Are Protected from Acetaminophen Hepatotoxicity Toxicol. Sci., June 1, 2003; 73(2): 220 - 234. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A H McGregor, L J More, K J Simpson, and D J Harrison Liver death and regeneration in paracetamol toxicity Human and Experimental Toxicology, April 1, 2003; 22(4): 221 - 227. [Abstract] [PDF]
|
|
|
|
|
|
T. R. Knight, Y.-S. Ho, A. Farhood, and H. Jaeschke Peroxynitrite Is a Critical Mediator of Acetaminophen Hepatotoxicity in Murine Livers: Protection by Glutathione J. Pharmacol. Exp. Ther., November 1, 2002; 303(2): 468 - 475. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
K. L. Muldrew, L. P. James, L. Coop, S. S. McCullough, H. P. Hendrickson, J. A. Hinson, and P. R. Mayeux Determination of Acetaminophen-Protein Adducts in Mouse Liver and Serum and Human Serum after Hepatotoxic Doses of Acetaminophen Using High-Performance Liquid Chromatography with Electrochemical Detection Drug Metab. Dispos., April 1, 2002; 30(4): 446 - 451. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
R. Snyder The International Symposium on Biological Reactive Intermediates Toxicol. Sci., April 1, 2002; 66(2): 173 - 175. [Full Text] [PDF]
|
|
|
|
|
|
S. U. Ruepp, R. P. Tonge, J. Shaw, N. Wallis, and F. Pognan Genomics and Proteomics Analysis of Acetaminophen Toxicity in Mouse Liver Toxicol. Sci., January 1, 2002; 65(1): 135 - 150. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
T. R. Knight, A. Kurtz, M. L. Bajt, J. A. Hinson, and H. Jaeschke Vascular and Hepatocellular Peroxynitrite Formation during Acetaminophen Toxicity: Role of Mitochondrial Oxidant Stress Toxicol. Sci., August 1, 2001; 62(2): 212 - 220. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. J. Beck, C. McLellan, R. L.-F. Lightle, M. A. Philbert, and C. Harris Spatial Glutathione and Cysteine Distribution and Chemical Modulation in the Early Organogenesis-Stage Rat Conceptus in Utero Toxicol. Sci., July 1, 2001; 62(1): 92 - 102. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. M. Lucas, G. Hennig, P. K. Dominick, H. E. Whiteley, J. C. Roberts, and S. D. Cohen Ribose Cysteine Protects Against Acetaminophen-Induced Hepatic and Renal Toxicity Toxicol Pathol, September 1, 2000; 28(5): 697 - 704. [Abstract] [PDF]
|
|
|
|
|
|
A. E. Mutlib, J. Shockcor, R. Espina, N. Graciani, A. Du, and L.-S. Gan Disposition of Glutathione Conjugates in Rats by a Novel Glutamic Acid Pathway: Characterization of Unique Peptide Conjugates by Liquid Chromatography/Mass Spectrometry and Liquid Chromatography/NMR J. Pharmacol. Exp. Ther., August 1, 2000; 294(2): 735 - 745. [Abstract] [Full Text]
|
|
|
|
|
|
F. A. Nicholls-Grzemski, I. C. Calder, B. G. Priestly, and P. C. Burcham Clofibrate-Induced in Vitro Hepatoprotection against Acetaminophen Is Not Due to Altered Glutathione Homeostasis Toxicol. Sci., July 1, 2000; 56(1): 220 - 228. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. H. Boulares, C. Giardina, M. S. Inan, E. A. Khairallah, and S. D. Cohen Acetaminophen Inhibits NF-{kappa}B Activation by Interfering with the Oxidant Signal in Murine Hepa 1-6 Cells Toxicol. Sci., June 1, 2000; 55(2): 370 - 375. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 G. L. Kearns, J. S. Leeder, and G. S. Wasserman Acetaminophen Intoxication During Treatment: What You Don't Know Can Hurt You Clinical Pediatrics, March 1, 2000; 39(3): 133 - 144. [Abstract] [PDF]
|
|
|
|
 |
|
 P.-G. Forkert, D. D'Costa, and M. El-Mestrah Expression and Inducibility of Alpha, Pi, and Mu Glutathione S-Transferase Protein and mRNA in Murine Lung Am. J. Respir. Cell Mol. Biol., January 1, 1999; 20(1): 143 - 152. [Abstract] [Full Text]
|
|
|
|
|
|
Y. Qiu, L. Z. Benet, and A. L. Burlingame Identification of the Hepatic Protein Targets of Reactive Metabolites of Acetaminophen in Vivo in Mice Using Two-dimensional Gel Electrophoresis and Mass Spectrometry J. Biol. Chem., July 10, 1998; 273(28): 17940 - 17953. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
W. F. Salminen Jr., S. M. Roberts, N. R. Pumford, and J. A. Hinson Immunochemical Comparison of 3'-Hydroxyacetanilide and Acetaminophen Binding in Mouse Liver Drug Metab. Dispos., March 1, 1998; 26(3): 267 - 271. [Abstract] [Full Text]
|
|
|
|
|
|
K. C. Turner and K. L. R. Brouwer In Vitro Mechanisms of Probenecid-Associated Alterations in Acetaminophen Glucuronide Hepatic Disposition Drug Metab. Dispos., September 1, 1997; 25(9): 1017 - 1021. [Abstract] [Full Text]
|
|
|
|
|
|
P.-G. Forkert, K. S. Collins, T. F. Dowsley, and G. M. Ross J. Pharmacol. Exp. Ther., June 1, 1997; 281(3): 1422 - 1430. [Abstract]
|
|
|
|
|
|
N. R. Pumford, N. C. Halmes, B. M. Martin, R. J. Cook, C. Wagner, and J. A. Hinson Covalent Binding of Acetaminophen to N-10-Formyl-Tetrahydrofolate Dehydrogenase in Mice J. Pharmacol. Exp. Ther., January 1, 1997; 280(1): 501 - 505. [Abstract] [Full Text]
|
|
|
|
|
|
S. S. T. Lee, J. T. M. Buters, T. Pineau, P. Fernandez-Salguero, and F. J. Gonzalez Role of CYP2E1 in the Hepatotoxicity of Acetaminophen J. Biol. Chem., May 17, 1996; 271(20): 12063 - 12067. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 H Shichi, D. Gaasterland, N. Jensen, and D. Nebert Ah locus: genetic differences in susceptibility to cataracts induced by acetaminophen Science, May 5, 1978; 200(4341): 539 - 541. [Abstract] [PDF]
|
|
|
|
|
|
D. M. Jerina and J. W. Daly Arene Oxides: A New Aspect of Drug Metabolism Science, August 16, 1974; 185(4151): 573 - 582. [PDF]
|
|
|
|
 |
|
 C. J. Henderson, C. R. Wolf, N. Kitteringham, H. Powell, D. Otto, and B. K. Park Increased resistance to acetaminophen hepatotoxicity in mice lacking glutathione S-transferase Pi PNAS, November 7, 2000; 97(23): 12741 - 12745. [Abstract] [Full Text] [PDF]
|
|
 |
 |
 |
|
 |
 |
 |
