Selective Protein Arylation and Acetaminophen-Induced Hepatotoxicity

Abstract

More than 20 years have passed since the early reports of acute hepatotoxicity with APAP overdose. During that period investigative research to discover the "mechanism" underlying the toxicity has been conducted in many species and strains of intact animals as well as in a variety of in vitro and culture systems. Such work has clarified the primary role of biotransformation and the protective role of GSH. Understanding the former provides explanations for the toxic interactions which may occur with alcohol or other xenobiotics, while understanding of the latter led to the development of antidotes for the treatment of acute poisoning. Acetaminophen (APAP)-induced hepatotoxicity: roles for protein arylation. Initiating events in toxicity require biotransformation of APAP to NAPQI followed by arylation of several important proteins with subsequent alteration of protein structure and function. The immediate consequence of the alterations is detectable in several organelles and these may represent multiple initiating events which are depicted as acting in concert to cause cell injury (large arrowheads). Arylation of cytosolic 58-ABP with subsequent translocation to the nucleus is depicted as a possible signaling mechanism for determining outcome at the cell or organ level (within dotted boundary). For simplicity NAPQI's potentials for oxidizing protein sulfhydryls and direct binding to DNA have been omitted. Significant light has also been shed on the biochemical and cellular events which accompany APAP-induced hepatotoxicity. However, such studies have not identified a unique mechanism of toxicity that is universally accepted. The recent identification of several protein targets which become arylated during toxicity--along with the findings that arylation of some of those target proteins results in loss of protein function--demonstrates that covalent binding does, indeed, have biological consequences and is not merely an indicator of the fleeting presence of reactive electrophiles. These observations further suggest that multiple independent insults to the cell may be involved in toxicity. it is now apparent that the concept of a multistage process that involves both initiation and progression events is appropriate for APAP toxicity, and it is unlikely that a unique initiating event will ever be identified. In light of recent findings it is more likely that a number of such cellular events occur very early after toxic overdosage, and that they collectively set in motion and perpetuate the biochemical, cellular, and molecular processes which will determine outcome. The importance of 58-ABP arylation with early, apparently selective, translocation to the nucleus remains to be elucidated. To date there is nothing to suggest that this represents an initiating event in toxicity. rather it is plausible that the translocation may play a role in signaling electrophile presence and in calling for cellular defense against electrophile insult. This is reflected in the hypothetical model presented in Fig. 3. Critical experimenta...

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Reduced acetaminophen-induced liver injury in mice by genetic disruption of IL-1 receptor antagonist

“…37,38 This process is the initial and irreversible step in the development of cell injury. 38,39 Among several adducts, selenium-binding protein with a molecular weight of 56 kDa, a major APAP adduct, reflects the amounts of generated NAPQI and APAP adducts, 40,41 and can determine the magnitude of APAP-induced direct liver injury. 2,3 IL-1ra KO-derived hepatocytes exhibited similar sensitivities to NAPQI as WT mouse-derived ones.…”

Influence of Feeding Schedule on 24-h Rhythm of Hepatotoxicity Induced by Acetaminophen in Mice

“…NAPQI is formed by cytochrome P450 in the liver (Dahlin et al, 1984) and induces liver damage via a chain of cellular events. These events include depletion of cellular GSH and covalent binding to cellular proteins (Cohen and Khairallah, 1997), recruitment and activation of macrophages (Laskin and Pendino, 1995), initiation of oxidative stress and oxidation of protein thiols (Jaeschke, 1990;Tirmenstein and Nelson, 1990), alteration of calcium homeostasis, and damage to nuclear DNA (Corcoran and Ray, 1992).…”