Extrahepatic Lesions Induced by Acetaminophen in the Mouse

Placke, Michael E.; Wyand, D. S.; Cohen, Steven D.

doi:10.1177/019262338701500401

Cited by 59 publications

(35 citation statements)

References 14 publications

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“…Male mice (10-12 weeks old) were fasted overnight and then treated with APAP (500 mg/kg i.p.) or vehicle (phosphate-buffered saline) for 1, 2, or 18 h. Mice were fasted because unfed mice exhibit more consistent responses to APAP than do fed mice (Placke et al, 1987;Lucas et al, 2000). Mice were sacrificed at the indicated time points.…”

Section: Methodsmentioning

confidence: 99%

Retinoid X Receptor α Regulates the Expression of Glutathione S-transferase Genes and Modulates Acetaminophen-Glutathione Conjugation in Mouse Liver

Dai

Chou

et al. 2005

Mol Pharmacol

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Nuclear receptors, including constitutive androstane receptor, pregnane X receptor, and retinoid X receptor (RXR), modulate acetaminophen (APAP)-induced hepatotoxicity by regulating the expression of phase I cytochrome P450 (P450) genes. It has not been fully resolved, however, whether they regulate APAP detoxification at the phase II level. The aim of the current study was to evaluate the role of RXR␣ in phase II enzyme-mediated detoxification of APAP. Wild-type and hepatocyte-specific RXR␣ knockout mice were treated with a toxic dose of APAP (500 mg/kg i.p.). Mutant mice were protected from APAPinduced hepatotoxicity, even though basal liver glutathione (GSH) levels were significantly lower in mutant mice compared with those of wild-type mice. High-performance liquid chromatography analysis of APAP metabolites revealed significantly greater levels of APAP-GSH conjugates in livers and bile of mutant mice compared with those of wild-type mice. Furthermore, hepatocyte RXR␣ deficiency altered the gene expression profile of the glutathione S-transferase (Gst) family. Basal expression of 13 of 15 Gst genes studied was altered in hepatocyte-specific RXR␣-deficient mice. This probably led to enhanced APAP-GSH conjugation and reduced accumulation of N-acetyl-p-benzoquinone imine, a toxic electrophile that is produced by biotransformation of APAP by phase I P450 enzymes. In conclusion, the data presented in this study define an RXR␣-Gst regulatory network that controls APAP-GSH conjugation. This report reveals a potential novel strategy to enhance the detoxification of APAP or other xenobiotics by manipulating Gst activity through RXR␣-mediated pathways.

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Section: Methodsmentioning

confidence: 99%

Retinoid X Receptor α Regulates the Expression of Glutathione S-transferase Genes and Modulates Acetaminophen-Glutathione Conjugation in Mouse Liver

Dai

Chou

et al. 2005

Mol Pharmacol

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“…PCM toxicity is one of the major causes of poisoning worldwide (Gunnell et al, 2000), and its overdose is commonly associated with hepatic (Nelson, 1995) and renal damages (Placke et al, 1987). PCM toxicity is mediated by the activity of its reactive metabolite known as N-acetyl-p-benzoquinoneimine (NAPQI), which is detoxified by intracellular glutathione (GSH) (Borne, 1995).…”

Section: Introductionmentioning

confidence: 99%

Nephroprotective effects of Zingiber zerumbet Smith ethyl acetate extract against paracetamol-induced nephrotoxicity and oxidative stress in rats

Hamid

Budin

et al. 2012

J. Zhejiang Univ. Sci. B

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Abstract:Paracetamol (PCM) overdose can cause nephrotoxicity with oxidative stress as one of the possible mechanisms mediating the event. In this study, the effects of ethyl acetate extract of Zingiber zerumbet rhizome [200 mg per kg of body weight (mg/kg) and 400 mg/kg] on PCM-induced nephrotoxicity were examined. Rats were divided into five groups containing 10 rats each. The control group received distilled water while other groups were treated with extract alone (400 mg/kg), PCM alone (750 mg/kg), 750 mg/kg PCM+200 mg/kg extract (PCM+ 200-extract), and 750 mg/kg PCM+400 mg/kg extract (PCM+400-extract), respectively, for seven consecutive days. The Z. zerumbet extract was given intraperitoneally concurrent with oral administration of PCM. Treatment with Z. zerumbet extract at doses of 200 and 400 mg/kg prevented the PCM-induced nephrotoxicity and oxidative impairments of the kidney, as evidenced by a significantly reduced (P<0.05) level of plasma creatinine, plasma and renal malondialdehyde (MDA), plasma protein carbonyl, and renal advanced oxidation protein product (AOPP). Furthermore, both doses were also able to induce a significant increment (P<0.05) of plasma and renal levels of glutathione (GSH) and plasma superoxide dismutase (SOD) activity. The nephroprotective effects of Z. zerumbet extract were confirmed by a reduced intensity of renal cellular damage, as evidenced by histological findings. Moreover, Z. zerumbet extract administered at 400 mg/kg was found to show greater protective effects than that at 200 mg/kg. In conclusion, ethyl acetate extract of Z. zerumbet rhizome has a protective role against PCM-induced nephrotoxicity and the process is probably mediated through its antioxidant properties.

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“…Acetaminophen overdose causes liver and kidney damage in some humans (Boyer and Rouff, 1971) and in experimental animals (Boyd and Bereczky, 1966;Mitchell et al, 1973). In mice, acetaminophen also causes toxicity in several other organs, including the nasal mucosa and lung (Placke et al, 1987;Jeffery and Haschek, 1988;Genter et al, 1998). The toxicity of acetaminophen is believed to be associated with P450-mediated generation of a toxic metabolite, N-acetyl-p-benzoquinone imine (Dahlin et al, 1984), which causes glutathione depletion and adduction with cellular macromolecules Potter et al, 1974).…”

mentioning

confidence: 99%

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

et al. 2004

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Acetaminophen overdose causes toxicity in liver and extrahepatic tissues. Although it is well established that cytochrome P450 enzymes play a critical role in the metabolic activation of acetaminophen, it is not yet clear whether acetaminophen toxicity in extrahepatic tissues is a consequence of hepatic biotransformation. The aim of this study was to determine whether extrahepatic acetaminophen toxicity is altered in a mouse model that has liver-specific deletion of the NADPH-cytochrome P450 reductase (Cpr) gene. Liver-specific Cpr-null (Null) mice were resistant to acetaminophen hepatotoxicity, and they showed faster acetaminophen clearance than did wildtype mice at a toxic acetaminophen dose (400 mg/kg i.p.). However, when circulating acetaminophen levels were made equivalent in the two strains, the severity of extrahepatic acetaminophen toxicity was decreased in the Null relative to that in the wild-type mice in the lung, kidney, and lateral nasal glands, although not in the nasal olfactory and respiratory mucosa. In the lung and liver, the decreased acetaminophen toxicity was accompanied by substantial decreases in the formation of acetaminophen-protein adducts in the Null mice; adducts were not detected in other tissues examined. These results indicate that acetaminophen toxicity in the nasal mucosa is not dependent on hepatic microsomal P450-catalyzed metabolic activation and that acetaminophen toxicity in the lung, kidney, and lateral nasal glands is at least partly caused by liver-derived acetaminophen metabolites.

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Extrahepatic Lesions Induced by Acetaminophen in the Mouse

Cited by 59 publications

References 14 publications

Retinoid X Receptor α Regulates the Expression of Glutathione S-transferase Genes and Modulates Acetaminophen-Glutathione Conjugation in Mouse Liver

Retinoid X Receptor α Regulates the Expression of Glutathione S-transferase Genes and Modulates Acetaminophen-Glutathione Conjugation in Mouse Liver

Nephroprotective effects of Zingiber zerumbet Smith ethyl acetate extract against paracetamol-induced nephrotoxicity and oxidative stress in rats

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

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