Temporal variation in hepatotoxicity and metabolism of acetaminophen in mice

Kim, Young C.; Lee, Soo J

doi:10.1016/s0300-483x(98)00046-8

Cited by 46 publications

(34 citation statements)

References 23 publications

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“…However, APAP metabolites are only found in the centrilobular areas of the liver following acute poisoning. As the time course of liver injury following APAP demonstrates, worsening liver injury and panlobular necrosis 8 -16 h after the completion of APAP metabolism in mice and humans, this supports a second mechanism in propagating liver injury (16).…”

Section: Discussionmentioning

confidence: 70%

P2X7 receptor-mediated purinergic signaling promotes liver injury in acetaminophen hepatotoxicity in mice

Hoque

Sohail

Salhanick

et al. 2012

American Journal of Physiology-Gastrointestinal and Liver Physi

124

111

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SC, Mehal WZ. P2x7 receptor-mediated purinergic signaling promotes liver injury in acetaminophen hepatotoxicity in mice. Am J Physiol Gastrointest Liver Physiol 302: G1171-G1179, 2012. First published March 1, 2012; doi:10.1152/ajpgi.00352.2011.-Inflammation contributes to liver injury in acetaminophen (APAP) hepatotoxicity in mice and is triggered by stimulation of immune cells. The purinergic receptor P2X7 is upstream of the nod-like receptor family, pryin domain containing-3 (NLRP3) inflammasome in immune cells and is activated by ATP and NAD that serve as damage-associated molecular patterns. APAP hepatotoxicity was assessed in mice genetically deficient in P2X7, the key inflammatory receptor for nucleotides (P2X7Ϫ/Ϫ), and in wild-type mice. P2X7Ϫ/Ϫ mice had significantly decreased APAP-induced liver necrosis. In addition, APAP-poisoned mice were treated with the specific P2X7 antagonist A438079 or etheno-NAD, a competitive antagonist of NAD. Pre-or posttreatment with A438079 significantly decreased APAP-induced necrosis and hemorrhage in APAP liver injury in wild-type but not P2X7Ϫ/Ϫ mice. Pretreatment with etheno-NAD also significantly decreased APAP-induced necrosis and hemorrhage in APAP liver injury. In addition, APAP toxicity in mice lacking the plasma membrane ectoNTPDase CD39 (CD39Ϫ/Ϫ) that metabolizes ATP was examined in parallel with the use of soluble apyrase to deplete extracellular ATP in wild-type mice. CD39Ϫ/Ϫ mice had increased APAP-induced hemorrhage and mortality, whereas apyrase also decreased APAP-induced mortality. Kupffer cells were treated with extracellular ATP to assess P2X7-dependent inflammasome activation. P2X7 was required for ATP-stimulated IL-1␤ release. In conclusion, P2X7 and exposure to the ligands ATP and NAD are required for manifestations of APAPinduced hepatotoxicity.CD39; nod-like receptor family, pryin domain containing-3, caspase-1; inflammasome; damage-associated molecular pattern ACETAMINOPHEN (APAP) overdose is the most common cause of acute liver failure in the Unites States and Europe (15,18,24). Furthermore, cases of acute hepatic failure due to APAP continue to rise (24). Toxicity is initiated by metabolism of APAP via reductive pathways to reactive metabolites. An antidote exists for patients early in the course of poisoning during this metabolism phase. However, with increased delays in administration of therapy, the frequency with which patients develop hepatocellular injury worsens.The initial, direct toxic injury induces an area of necrosis in the centrilobular regions. Liver injury is propagated by an inflammatory response after the drug has been metabolized and the initial centrilobular injury has occurred (23). The nature of this inflammatory response has been the subject of significant investigation in the past several years.Prior research by our group indicates that inflammasome activation is a crucial initiating step in the propagation of APAP-induced hepatic injury (10). Proinflammatory cytokines IL-1␤ and IL-18 are thought to be crucial to the prop...

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Section: Discussionmentioning

confidence: 70%

P2X7 receptor-mediated purinergic signaling promotes liver injury in acetaminophen hepatotoxicity in mice

Hoque

Sohail

Salhanick

et al. 2012

American Journal of Physiology-Gastrointestinal and Liver Physi

124

111

View full text Add to dashboard Cite

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“…Plasma concentrations of APAP and its metabolites were measured using an HPLC method described elsewhere (7). Briefly, plasma was mixed with an aliquot of acetonitrile containing theophylline as an internal standard.…”

Section: Measurement Of Apap Metabolites In Plasmamentioning

confidence: 99%

Alteration in Metabolism and Toxicity of Acetaminophen Upon Repeated Administration in Rats

et al. 2009

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Abstract. Our previous studies showed that administration of a subtoxic dose of acetaminophen (APAP) to female rats increased generation of carbon monoxide from dichloromethane, a metabolic reaction catalyzed mainly by cytochrome P450 (CYP) 2E1. In this study we examined the changes in metabolism and toxicity of APAP upon repeated administration. An intraperitoneal dose of APAP (500 mg/kg) alone did not increase aspartate aminotransferase, alanine aminotransferase, or sorbitol dehydrogenase activity in serum, but was significantly hepatotoxic when the rats had been pretreated with an identical dose of APAP 18 h earlier. The concentrations and disappearance of APAP and its metabolites in plasma were monitored for 8 h after the treatment. APAP pretreatment reduced the elevation of APAP-sulfate, but increased APAP-cysteine concentrations in plasma. APAP or APAP-glucuronide concentrations were not altered. Administration of a single dose of APAP 18 h before sacrifice increased microsomal CYP activities measured with p-nitrophenol, p-nitroanisole, and aminopyrine as probes. Expression of CYP2E1, CYP3A, and CYP1A proteins in the liver was also elevated significantly. The results suggest that administration of APAP at a subtoxic dose may result in an induction of hepatic CYP enzymes, thereby altering metabolism and toxicological consequences of various chemical substances that are substrates for the same enzyme system.

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“…18) Briefly, plasma was mixed with an aliquot of acetonitrile containing theophylline as an internal standard. After extraction and centrifugation, the resulting supernatant was evaporated to dryness under nitrogen.…”

Section: Animals and Treatmentsmentioning

confidence: 99%

Effects of Dimethylsulfoxide on Metabolism and Toxicity of Acetaminophen in Mice

Yoon

Kim

Lee

et al. 2006

Biological & Pharmaceutical Bulletin

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Dimethylsulfoxide (DMSO) is frequently used as a solvent in various in vivo and in vitro experiments. The use of this solvent is favored especially when physicochemical properties of a test compound have not been well characterized such as in the case of natural products. But DMSO is not biologically inert. DMSO has numerous pharmacological effects, the most well-known of which is hydroxyl radical scavenging capacity. Therefore, it is suspected that toxicological implications of the interaction of DMSO with a xenobiotic, either directly or indirectly via body system, would be complex.Acetaminophen (APAP), a widely used analgesic-antipyretic, is detoxified rapidly through formation of sulfate and glucuronide conjugates. 1) However, at large doses this drug is increasingly converted into a reactive metabolite, Nacetyl-p-benzoquinonimine (NAPQI). The metabolic activation of APAP in human is mediated by CYP2E1, 1A2 and 3A4.2,3) The relative contribution of each CYP isozyme to formation of the toxic metabolite is not clear, however, it has been generally accepted that CYP2E1 has the principal role in metabolic activation of this drug both in human and rodents. The reactive metabolite is normally detoxified by conjugation with glutathione (GSH), subsequently resulting in generation of APAP-mercapturate via APAP-cysteine. When generation of the reactive metabolite exceeds the availability of GSH for conjugation reaction, covalent binding of the metabolite to macromolecules may result, an event that correlates with induction of hepatic necrosis.4) Therefore, the most important determinants for induction of APAP toxicity are the metabolic activities catalyzing its activation and the effectiveness of GSH conjugation reaction.It has been shown that induction of APAP hepatotoxicity may be decreased by a dose of DMSO in mice 5) and also in hamsters. 6) In mice DMSO was found to decrease covalent binding of APAP metabolites to hepatic protein, but the microsomal aniline hydroxylase activity was rather increased. 7)Accordingly, the authors suggested that the protective effect of DMSO was due to interaction of DMSO with free radicals or reactive APAP metabolites. Later studies revealed that the protection provided by DMSO was tissue-specific, which would exclude the possibility of involvement of a nonspecific mechanism such as scavenging of free radicals. 8) Also DMSO was shown to inhibit the biliary concentration of APAP-GSH and the microsomal dimethylnitrosamine Ndemethylase activity. 9) Therefore, it appears that the protective effect of DMSO against APAP liver toxicity is associated with inhibition of CYP-dependent activation of this drug. Meanwhile, conflicting results were demonstrated in studies examining the effects of DMSO on metabolism and toxicity of other xenobiotics that are also metabolically activated by CYP2E1. For instance, DMSO was shown to enhance the hepatotoxicity of carbon tetrachloride (CCl 4 ), 10) while other studies demonstrated reduction of CCl 4 -induced hepatotoxicity in rats and mice. 11,12) Differ...

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Temporal variation in hepatotoxicity and metabolism of acetaminophen in mice

Cited by 46 publications

References 23 publications

P2X7 receptor-mediated purinergic signaling promotes liver injury in acetaminophen hepatotoxicity in mice

P2X7 receptor-mediated purinergic signaling promotes liver injury in acetaminophen hepatotoxicity in mice

Alteration in Metabolism and Toxicity of Acetaminophen Upon Repeated Administration in Rats

Effects of Dimethylsulfoxide on Metabolism and Toxicity of Acetaminophen in Mice

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