• Korean Journal of Clinical Pharmacy
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• v.8 no.2
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• pp.143-146
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• 1998

Acetaminophen (APAP) suppositories with active ingredients, i.e., polyethylene glycol (PEG), Witepsol H-15 (WH), were prepared for hospital use and investigated on their drug release characteristics and pharmacokinetics. WH was employed as oil-soluble base with an aim of reducing fragility and mucosa irritancy that are common drawbacks found in PEG suppositories. Also hollow type suppository was tried as compared with conventional type suppository. Drug release tests revealed that in most formulations, more than $80\%$ of loaded APAP were released within 20 minutes, except for APAP-WH hollow type suppositories. Significant differences in the plasma concentration profile were observed among four type suppositories. $T_{max}$ of APAP-PEG and APAP-WH suppositories were 90 and 60 minutes, respectively, in hollow types. APAP-WH hollow type suppositories demonstrated fast absorption rates of APAP as compared with those of APAP-PEG suppositories. No burst effect was observed from APAP-WH suppository in contrast to APAP conventional type suppository, whereas AUCs of all the suppositories were similar. APAP-WH hollow type suppository may be an useful dosage form for hospital use.

• Molecules and Cells
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• v.38 no.10
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• pp.843-850
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• 2015

The1hepatic cell death induced by acetaminophen (APAP) is closely related to cellular adenosine triphosphate (ATP) depletion, which is mainly caused by mitochondrial dysfunction. Adenosine monophosphate (AMP)-activated protein kinase (AMPK) is a key sensor of low energy status. AMPK regulates metabolic homeostasis by stimulating catabolic metabolism and suppressing anabolic pathways to increase cellular energy levels. We found that the decrease in active phosphorylation of AMPK in response to APAP correlates with decreased ATP levels, in vivo. Therefore, we hypothesized that the enhanced production of ATP via AMPK stimulation can lead to amelioration of APAP-induced liver failure. A769662, an allosteric activator of AMPK, produced a strong synergistic effect on AMPK Thr172 phosphorylation with APAP in primary hepatocytes and liver tissue. Interestingly, activation of AMPK by A769662 ameliorated the APAP-induced hepatotoxicity in C57BL/6N mice treated with APAP at a dose of 400 mg/kg intraperitoneally. However, mice treated with APAP alone developed massive centrilobular necrosis, and APAP increased their serum alanine aminotransferase and aspartate aminotransferase levels. Furthermore, A769662 administration prevented the loss of intracellular ATP without interfering with the APAP-mediated reduction of mitochondrial dysfunction. In contrast, inhibition of glycolysis by 2-deoxy-glucose eliminated the beneficial effects of A769662 on APAP-mediated liver injury. In conclusion, A769662 can effectively protect mice against APAP-induced liver injury through ATP synthesis by anaerobic glycolysis. Furthermore, stimulation of AMPK may have potential therapeutic application for APAP overdose.

• Food Science and Biotechnology
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• v.15 no.5
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• pp.752-755
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• 2006

This study was carried out to investigate the effects of ash tree leaf extract (ALE) on acetaminophen (APAP)-induced hepatotoxicity in mice. Hepatoprotective effects were detected by biochemical analysis of hepatic enzymes and histopathological examination of the liver. BALB/c mice were divided into three groups: 'normal' control mice, APAP-treated control mice, and mice pretreated with ALE and treated with APAP. A single dose of APAP markedly increased levels of plasma aspartate aminotransferase (AST) and alanine aminotransferase (ALT). Light micrographs of liver cells stained with hematoxylin and eosin showed that APAP induced severe centrilobular necrosis, degeneration, and infiltration by inflammatory cells. Moreover, APAP caused the numbers of TUNEL-positive hepatocytes to increase and caused glycogen content to decrease as observed by Periodic acid-Schiff stain. However, pretreatment with ALE for 7 days prior to the administration of APAP significantly decreased plasma levels of AST and ALT. Histological findings demonstrated that ALE pretreatment alleviated APAP-induced liver damage, and induced the regeneration of liver tissue and restoration of glycogen. These results indicate that ash tree leaf extract exerts a protective effect against APAP-hepatotoxicity induced injury.

• Korean Journal of Food Science and Technology
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• v.39 no.6
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• pp.688-693
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• 2007

The hepatoprotective effects of water extracts composed of Adenophora triphylla var japonica Hara (ATJH) on acetaminophen (APAP)-induced hepatotoxicity were investigated in vivo and in vivo. The effects of ATJH on liver toxicity induced by APAP were assessed by blood biochemical and histopathological analyses. APAP treatment (350 mg/kg) caused severe liver injury in mice as indicated by their significantly elevated plasma aspartate aminotransferase (AST) and alanine aminotransferase (ALT) levels. Pretreatment with ATJH for 3 or 7 days attenuated the increases in ALT and AST when challenged with APAP. The reductions in viability caused by high dose of APAP (450 mg/kg) in vivo were reversed by pretreatment with ATJH. These protective effects of ATJH against APAP-induced toxicity were consistent with the results from the histopathological examinations. We next examined the effects of ATJH on the gene expression of glutathione S-transferases (GSTs) that detoxify the metabolic intermediates of APAP in H4IIE cells. The hepatic GST protein levels [$\alpha$ class (GSTA2, GSTA3/5)] were significantly elevated in a dose-dependent manner by ATJH treatment. In summary, ATJH is effective at protecting against APAP-induced hepatotoxicity by GST induction, implying that ATJH should be considered a potential chemopreventive agent.

• Toxicological Research
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• v.14 no.2
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• pp.151-156
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• 1998

Acetaminophen (APAP) and gentamicin are widely used for many patients, but little in-formation is available regarding the combined effects of APAP and gentamicin. This study was aimed to investigate the potent nephrotoxicity following combined-treatment with APAP and gentamicin. Serum biochemical parameters and histopathological changes in the kidney were observed in female SD rats after continuous daily treatment with either 600 mg/kg/day APAP, and/or 300 mg/kg/day gentamicin for 3 days, and compared with saline sham-treated control animals. APAP and gentamicin combination-treated rats exhibited inconsistent increasing tendency in blood urea nitrogen (BUN) by 96 hours after the last treatment, compared to control or the animals treated with each drug. The relative kidney weights were also increased. Histopathological findings of kidneys revealed that necrosis of proximal convoluted tubules were higher in rats treated with APAP and gentamicin combination than the rats treated with each drug alone. These results suggest that combination use of both drugs have more severe nephrotoxicity than treating each drug alone.

• Natural Product Sciences
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• v.18 no.2
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• pp.121-129
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• 2012

Hepatoprotective effects of methanol extract and alisol B 23-acetate of Alisma orientale were studied in acetaminophen (APAP)-treated rats. APAP increased hepatic content of lipid peroxide, which was suppressed by methanol extract and alisol B 23-acetate. The liver of rats treated with APAP had higher P-450, aminopyrine N-demethylase and aniline hydroxylase activities than those of normal control rats. The increases in hepatic drug metabolizing enzymes by the i.p. injection of APAP were significantly alleviated by the administration of methanol extract or alisol B 23-acetate. The injection of APAP also resulted in a substantial reduction of hepatic glutathione content and glutathione S-transferase activity, and the decreases were partially, but significantly, restrained by the oral administration of methanol extract prior to the i.p. injection of APAP. Hepatic activities of glutathione reductase (GR) and ${\gamma}$-glutamylcystein synthetase ${\gamma}$-GCS) were also decreased significantly in APAP-treated rats. The decreases in hepatic GR and ${\gamma}$-GCS activities by APAP injection were improved partially, but significantly, with administration of methanol extract of A. orientale. Treatment with alisol B 23-acetate also improved the hepatic ${\gamma}$-GCS activity significantly, but not GR.

• Journal of Microbiology and Biotechnology
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• v.32 no.11
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• pp.1447-1453
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• 2022

Prohibitin 1 (Phb1) is a pleiotropic protein, located mainly in the mitochondrial inner membrane and involved in the regulation of cell proliferation and the stabilization of mitochondrial protein. Acetaminophen (APAP) is one of the most commonly used over-the-counter analgesics worldwide. However, at high dose, the accumulation of N-acetyl-p-benzoquinone imine (NAPQI) can lead to APAP-induced hepatotoxicity. In this study, we sought to understand the regulation of mRNA expression in relation to APAP and GSH metabolism by Phb1 in normal mouse AML12 hepatocytes. We used two different Phb1 silencing levels: high-efficiency (HE, >90%) and low-efficiency (LE, 50-60%). In addition, the siRNA-transfected cells were further pretreated with 0.5 mM of Sadenosylmethionine (SAMe) for 24 h before treatment with APAP at different doses (1-2 mM) for 24 h. The expression of APAP metabolism-related and antioxidant genes such as Cyp2e1 and Ugt1a1 were increased during SAMe pretreatment. Moreover, SAMe increased intracellular GSH concentration and it was maintained after APAP treatment. To sum up, Phb1 silencing and APAP treatment impaired the metabolism of APAP in hepatocytes, and SAMe exerted a protective effect against hepatotoxicity by upregulating antioxidant genes.

• Journal of Ginseng Research
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• v.43 no.1
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• pp.10-19
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• 2019

Background: Frequent overdose of paracetamol (APAP) has become the major cause of acute liver injury. The present study was designed to evaluate the potential protective effects of ginsenoside Rk1 on APAP-induced hepatotoxicity and investigate the underlying mechanisms for the first time. Methods: Mice were treated with Rk1 (10 mg/kg or 20 mg/kg) by oral gavage once per d for 7 d. On the 7th d, allmice treated with 250mg/kg APAP exhibited severeliverinjury after 24 h, and hepatotoxicitywas assessed. Results: Our results showed that pretreatment with Rk1 significantly decreased the levels of serum alanine aminotransferase, aspartate aminotransferase, tumor necrosis factor, and interleukin-$1{\beta}$ compared with the APAP group. Meanwhile, hepatic antioxidants, including superoxide dismutase and glutathione, were elevated compared with the APAP group. In contrast, a significant decrease in levels of the lipid peroxidation product malondialdehyde was observed in the ginsenoside Rk1-treated group compared with the APAP group. These effects were associated with a significant increase of cytochrome P450 E1 and 4-hydroxynonenal levels in liver tissues. Moreover, ginsenoside Rk1 supplementation suppressed activation of apoptotic pathways by increasing Bcl-2 and decreasing Bax protein expression levels, which was shown using western blotting analysis. Histopathological observation also revealed that ginsenoside Rk1 pretreatment significantly reversed APAP-induced necrosis and inflammatory infiltration in liver tissues. Biological indicators of nitrative stress, such as 3-nitrotyrosine, were also inhibited after pretreatment with Rk1 compared with the APAP group. Conclusion: The results clearly suggest that the underlying molecular mechanisms in the hepatoprotection of ginsenoside Rk1 in APAP-induced hepatotoxicity may be due to its antioxidation, antiapoptosis, anti-inflammation, and antinitrative effects.

• Toxicological Research
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• v.29 no.3
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• pp.165-172
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• 2013

Acetaminophen (APAP) known as paracetamol is the main ingredient in Tylenol, which has analgesic and anti-pyretic properties. Inappropriate use of APAP causes major morbidity and mortality secondary to hepatic failure. Overdose of APAP depletes the hepatic glutathione (GSH) rapidly, and the metabolic intermediate leads to hepatocellular death. This article reviews the mechanisms of hepatotoxicity and provides an overview of current research studies. Pharmacokinetics including metabolism (activation and detoxification), subsequent transport (efflux)-facilitating excretion, and some other aspects related to toxicity are discussed. Nuclear factor erythroid 2-related factor 2 (Nrf2)-regulated gene battery plays a critical role in the multiple steps associated with the mitigation of APAP toxicity. The role of Nrf2 as a protective target is described, and potential natural products inhibiting APAP toxicity are outlined. This review provides an update on the mechanism of APAP toxicity and highlights the beneficial role of Nrf2 and specific natural products in hepatoprotection.