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Version 2; Peer Review: 2 Approved] Swetha Rudraiah, José E F1000Research 2016, 5(F1000 Faculty Rev):1698 Last updated: 17 JUL 2019 REVIEW From hepatoprotection models to new therapeutic modalities for treating liver diseases: a personal perspective [version 2; peer review: 2 approved] Swetha Rudraiah, José E. Manautou Toxicology Program, Department of Pharmaceutical Sciences, School of Pharmacy, University of Connecticut, Storrs, CT, USA First published: 14 Jul 2016, 5(F1000 Faculty Rev):1698 ( Open Peer Review v2 https://doi.org/10.12688/f1000research.8609.1) Latest published: 19 Jul 2016, 5(F1000 Faculty Rev):1698 ( https://doi.org/10.12688/f1000research.8609.2) Reviewer Status Abstract Invited Reviewers A variety of rodent models of hepatoprotection have been developed in 1 2 which tolerance to acetaminophen-induced hepatotoxicity occurs. Autoprotection/heteroprotection is a phenomenon where prior exposure to a mildly toxic dose of toxicant confers protection against a subsequently version 2 administered higher dose of the same toxicant (as in the case of published autoprotection) or to a different toxicant (referred to as heteroprotection). 19 Jul 2016 Multiple mechanisms regulate this adaptive response, including hepatocellular proliferation, proteostasis, enhanced expression of version 1 cytoprotective genes, and altered tissue immune response. In this review, published we will discuss recent findings that highlight the complexity of these 14 Jul 2016 adaptive mechanisms and we also outline the usefulness of these findings to devise therapeutic and/or diagnostic tools for acetaminophen-induced liver damage in patients. F1000 Faculty Reviews are written by members of the prestigious F1000 Faculty. They are Keywords commissioned and are peer reviewed before hepatoprotection , liver diseases , acetaminophen , acute liver failure , APAP toxicity publication to ensure that the final, published version is comprehensive and accessible. The reviewers who approved the final version are listed with their names and affiliations. 1 Philip Burcham, University of Western Australia, Nedlands, Australia 2 Udayan Apte, University of Kansas Medical Center, Kansas City, USA Any comments on the article can be found at the end of the article. Page 1 of 8 F1000Research 2016, 5(F1000 Faculty Rev):1698 Last updated: 17 JUL 2019 Corresponding author: José E. Manautou ([email protected]) Competing interests: The authors declare that they have no competing interests. Grant information: All work from the laboratory of Dr José E. Manautou and unpublished observations described here were supported by The National Institutes of Health Grant DK069557. Copyright: © 2016 Rudraiah S and Manautou JE. This is an open access article distributed under the terms of the Creative Commons Attribution Licence, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. How to cite this article: Rudraiah S and Manautou JE. From hepatoprotection models to new therapeutic modalities for treating liver diseases: a personal perspective [version 2; peer review: 2 approved] F1000Research 2016, 5(F1000 Faculty Rev):1698 ( https://doi.org/10.12688/f1000research.8609.2) First published: 14 Jul 2016, 5(F1000 Faculty Rev):1698 (https://doi.org/10.12688/f1000research.8609.1) Page 2 of 8 F1000Research 2016, 5(F1000 Faculty Rev):1698 Last updated: 17 JUL 2019 The advent of high-throughput gene microarray and proteomic REVISED Amendments from Version 1 analysis has facilitated the identification of global changes in gene This version includes an updated Figure 1 to correct errors and protein expression. Using these modern tools, novel mecha- introduced by F1000 Research during the production of the figure nisms implicated in adaptation to APAP toxicity have been iden- in Version 1. tified in the rodent models of autoprotection/heteroprotection11–17. See referee reports An update on the experimental models of hepatoprotection (both autoprotection and heteroprotection) (summarized in Figure 1) and their potential diagnostic/therapeutic usefulness in the prognosis and treatment of APAP-induced hepatotoxicity will be summarized in the current review. Introduction Acetaminophen (APAP) continues to be one of the most commonly Autoprotection and heteroprotection used analgesic and antipyretic agents in the U.S. and Great Britain. Autoprotection/heteroprotection is an experimental approach Its therapeutic benefits were first described more than a century employed to modulate APAP hepatotoxicity in rodents. Autopro- ago. However, APAP poisoning and its related hepatotoxicity were tection is the resistance to toxicant re-exposure following acute, first recognized in Great Britain1 and later in the U.S.2. APAP usage mild injury with the same toxicant, whereas in heteroprotection, the and popularity increased after aspirin was implicated in over 80% of initial toxicant used is different from the second one. In their pio- Reye’s syndrome cases in children. As APAP usage increased, the neering work, Mehendale and colleagues first demonstrated auto- incidence of APAP-induced hepatotoxicity increased concurrently. protection in rats in the early 1990s using the hepatotoxicant carbon In a retrospective study from 1994 to 1996, APAP-induced hepa- 18 tetrachloride (CCl4) . Similarly, studies conducted by our group totoxicity comprised about 25% of acute liver failure (ALF) cases have demonstrated both autoprotection/heteroprotection in mice and in the U.S.3. By the early 2000s, nearly 50% of all ALF cases from that pretreatment of mice with various xenobiotics with different all etiologies were due to APAP use or misuse4. Alarmingly, these modes of action results in considerable reduction in the severity of statistics have remained fairly constant over the past decade; APAP APAP toxicity11,17. Administration of subtoxic doses of clofibrate use continues to be the most common cause of ALF in western (CFB), an activator of the peroxisome proliferator-activated recep- countries with no clear improvement in sight4,5. The potential for tor alpha (PPARα), protects mice from APAP hepatotoxicity (APAP APAP-related morbidity and mortality combined with the drug’s heteroprotection)17. Similarly, the APAP heteroprotection phenom- popularity and unrestricted access poses a significant human health enon has also been demonstrated with hepatotoxicants such as problem. 19 20,21 20 thioacetamide , CCl4 , chloroform, and bromobenzene . Results from initial studies using repeated doses of CFB show that protec- The current treatments for ALF due to APAP include either tion against APAP toxicity is associated with the prevention of GSH administration of the glutathione (GSH) precursor N-acetyl depletion and less covalent binding of the reactive intermediate of cysteine (NAC) or orthotopic liver transplantation (OLT) in those APAP with the cellular proteins17. A subsequent study showed that patients where NAC is ineffective. NAC increases the availability a single dose of CFB prior to intoxication with APAP also protects of intracellular cysteine, which in turn enhances the GSH formation against APAP hepatotoxicity, but neither produces changes in reac- rate. Thus, replenishment of cellular GSH is the main mechanism tive intermediate covalent binding nor GSH depletion22. Addition- through which NAC confers protection against APAP-induced liver ally, PPARα activation is a requirement for this response, since the injury. There are limitations associated with antidotal NAC treat- PPARα knockout mice are not afforded protection by CFB23. ment, particularly in unintentional APAP-overdose patients who do not report to a doctor until they feel discomfort. NAC is effec- In addition to APAP heteroprotection, we also demonstrated that tive when administered during the early stages (up to 24 hours) APAP at a mildly toxic dose protects mice against hepatotoxicity after APAP overdose, although symptoms frequently do not occur from higher doses of APAP (APAP autoprotection)11. Resistance until later5. OLT remains an ultimate choice of treatment in severe to APAP-induced liver injury is also observed with repeated expo- cases but is associated with high cost and limited availability of sure to APAP in rats and humans24,25. Shayiq et al., while describ- donor livers, also with confounded morbidity and mortality6. These ing the incremental dose model of APAP autoprotection in mice, long-standing limitations have prompted extensive research aimed introduced a clinical case of a physician addicted to a prescription at devising not only new measures to reduce the risk of APAP pain medication containing a combination of an opiate and APAP25. hepatotoxicity but also new treatment options. The physician claimed to have consumed 200 tablets per day in the later stages of his addiction (about 65 g of APAP) with no apparent Despite decades of considerable effort and steady progress towards liver damage, thus demonstrating a profound tolerance to APAP. In understanding the pathophysiological basis of APAP hepatotoxicity a later study, healthy adults given 4 g APAP per day over a period of and hepatoprotection, an evolution of novel therapeutics has yet 14 days showed elevations in plasma alanine aminotransferase (ALT) to be realized. Significant efforts are underway to investigate the activity around days 7 to 8 that subsequently decreased towards importance of regenerative therapies in ALF patients4,5,7–10. Apte day 1426. These studies clearly show that adaptation to hepatocyte et al. show β-catenin activation as one of the
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