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      Quantitative In Silico analysis of transient metabolism of acetaminophen and associated causes of hepatotoxicity in humans

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          Abstract

          Purpose

          Although safe at therapeutic levels, excess intake of acetaminophen can lead to hepatic injury or acute liver failure (ALF). A number of different factors influence metabolism and hepatotoxicity of acetaminophen in patients. Three of the most important are a patient’s physiological response to fasting, alcohol consumption, and chronic acetaminophen consumption. The molecular and enzymatic underpinnings for these processes have been extensively studied. The purpose of this study is to examine and quantify the effects of the noted conditions, provide possible reasons for conflicting clinical observations, and examine dangers associated with uptake of therapeutic doses of acetaminophen.

          Methods

          In order to gain a better understanding of the transient hepatic changes associated with each physiological and nutritional process, examine risks of ALF associated with individuals based on their unique lifestyle and health issues, and predict improved dosing strategies, a multi-compartmented physiologically-based pharmacokinetic (PBPK) model of acetaminophen metabolism in adult humans was developed. By varying the parameters of this model, changes in metabolism of acetaminophen and its toxic byproducts for a variety of medically relevant conditions were assessed.

          Results

          Simulated results indicate that in case of chronic ingestion of acetaminophen, the increased rate of glucuronidation plays a significant role in protecting patients from liver damage following uptake of excessive quantities. Analysis of metabolism of acetaminophen in persons who have imbibed excessive amounts of alcohol show that the primary reason for hepatotoxicity in such individuals is decreased availability of glutathione in the liver and not the observed increased production of toxic byproducts. When the glutathione depleting effects of alcohol consumption are combined with those associated with chronic acetaminophen use, intake of slightly higher quantities than the recommended therapeutic doses of acetaminophen can result in initiation of hepatotoxicity.

          Conclusions

          The results of simulations show that, in healthy and well-fed individuals, chronic uptake of acetaminophen doses even five times the therapeutic recommendations should be safe. However, in persons who have diminished hepatic glutathione regeneration capacities, depending on the magnitude of this deleterious shortcoming, minor overdoses can result in hepatotoxicity. Hence, it can be concluded that for such persons, acetaminophen is just as toxic as any other compound that would generate reactive oxidative species.

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          Most cited references104

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          Biologic and pharmacologic regulation of mammalian glutathione synthesis.

          Glutathione (L-gamma-glutamyl-L-cysteinylglycine, GSH) is synthesized from its constituent amino acids by the sequential action of gamma-glutamylcysteine synthetase (gamma-GCS) and GSH synthetase. The intracellular GSH concentration, typically 1-8 mM, reflects a dynamic balance between the rate of GSH synthesis and the combined rate of GSH consumption within the cell and loss through efflux. The gamma-GCS reaction is rate limiting for GSH synthesis, and regulation of gamma-GCS expression and activity is critical for GSH homeostasis. Transcription of the gamma-GCS subunit genes is controlled by a variety of factors through mechanisms that are not yet fully elucidated. Glutathione synthesis is also modulated by the availability of gamma-GCS substrates, primarily L-cysteine, by feedback inhibition of gamma-GCS by GSH, and by covalent inhibition of gamma-GCS by phosphorylation or nitrosation. Because GSH plays a critical role in cellular defenses against electrophiles, oxidative stress and nitrosating species, pharmacologic manipulation of GSH synthesis has received much attention. Administration of L-cysteine precursors and other strategies allow GSH levels to be maintained under conditions that would otherwise result in GSH depletion and cytotoxicity. Conversely, inhibitors of gamma-GCS have been used to deplete GSH as a strategy for increasing the sensitivity of tumors and parasites to certain therapeutic interventions.
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            Acetaminophen hepatotoxicity.

            Acetaminophen is a commonly used antipyretic and analgesic agent. It is safe when taken at therapeutic doses; however, overdose can lead to serious and even fatal hepatotoxicity. The initial metabolic and biochemical events leading to toxicity have been well described, but the precise mechanism of cell injury and death is unknown. Prompt recognition of overdose, aggressive management, and administration of N-acetylcysteine can minimize hepatotoxicity and prevent liver failure and death. Liver transplantation can be lifesaving for those who develop acute liver failure.
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              Regulation of hepatic glutathione synthesis: current concepts and controversies.

              Paul Lu (1999)
              Glutathione (GSH) is an important intracellular peptide with multiple functions ranging from antioxidant defense to modulation of cell proliferation. GSH is synthesized in the cytosol of all mammalian cells in a tightly regulated manner. The major determinants of GSH synthesis are the availability of cysteine, the sulfur amino acid precursor, and the activity of the rate-limiting enzyme, gamma-glutamylcysteine synthetase (GCS). In the liver, major factors that determine the availability of cysteine are diet, membrane transport activities of the three sulfur amino acids cysteine, cystine and methionine, and the conversion of methionine to cysteine via the trans-sulfuration pathway. Many conditions alter GSH level via changes in GCS activity and GCS gene expression. These include oxidative stress, activators of Phase II detoxifying enzymes, antioxidants, drug-resistant tumor cell lines, hormones, cell proliferation, and diabetes mellitus. Since the molecular cloning of GCS, much has been learned about the regulation of this enzyme. Both transcriptional and post-transcriptional mechanisms modulate the activity of this critical cellular enzyme.--Lu, S. C. Regulation of hepatic glutathione synthesis: current concepts and controversies.
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                Author and article information

                Contributors
                navid1@llnl.gov
                ng34@llnl.gov
                stewart66@llnl.gov
                wong105@llnl.gov
                lightstone1@llnl.gov
                Journal
                In Silico Pharmacol
                In Silico Pharmacol
                In Silico Pharmacology
                Springer Berlin Heidelberg (Berlin/Heidelberg )
                2193-9616
                4 November 2013
                4 November 2013
                2013
                : 1
                : 14
                Affiliations
                Biosciences & Biotechnology Division, Physical and Life Sciences Directorate, Lawrence Livermore National Laboratory, Livermore, CA USA
                Article
                14
                10.1186/2193-9616-1-14
                4750864
                9e68dc63-2424-4e07-8832-8342fa8bba97
                © Navid et al.; licensee Springer. 2013

                This article is published under license to BioMed Central Ltd. This is an open access article distributed under the terms of the Creative Commons Attribution License ( http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

                History
                : 2 July 2013
                : 10 October 2013
                Categories
                Original Research
                Custom metadata
                © The Author(s) 2013

                pharmacokinetic modeling,pbpk,acetaminophen,acute liver failure,admet,alcohol,malnutrition

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