Detecting mRNA Predictors of Acetaminophen-Induced Hepatotoxicity in Mouse Blood Using Quantitative Real-Time PCR

Kanno, Syu‐ichi; Tomizawa, Ayako; Yomogida, Shin

doi:10.1248/bpb.b15-00734

Cited by 7 publications

(11 citation statements)

References 33 publications

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“…On the other hand, when inflammation was caused by hepatic damage, anti-inflammatory cytokines as well as pro-inflammatory cytokines were induced 37 , 38 . An increase in the mRNA expression of the Il10 gene, which is a well-known anti-inflammatory cytokine, after APAP administration was reported in mice 30 , 31 . Kanno et al showed that mRNA levels of the Il10 gene in the blood were higher in mice with more severe APAP-induced toxicity 31 ; therefore, the decreased Il10 level in the EEBGP group might be largely attributable to the decreased necrosis rather than a direct effect of EEBGP on Il10 expression in the present study.…”

Section: Discussionmentioning

confidence: 98%

“…However, massive activation of an inflammatory response impairs normal hepatocytes, resulting in expansion of the necrosis area 23 , 24 , 25 . Increased levels of cytokines such as interleukin (IL)-1β, IL-6, and IL-10 and chemokines such as CC-motif chemokine ligand 2 (CCL2) and CXC-motif chemokine ligand 2 (CXCL2) were observed in the liver after APAP administration 26 , 27 , 28 , 29 , 30 , 31 . APAP-induced hepatocellular necrosis in mice decreased when IL-1β production or signaling 26 , 27 , 28 or CCL2 signaling 29 was disrupted.…”

Section: Introductionmentioning

confidence: 99%

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Brazilian green propolis suppresses acetaminophen-induced hepatocellular necrosis by modulating inflammation-related factors in rats

et al. 2018

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Propolis is a resin-like material produced by honey bees from bud exudates and sap of plants and their own secretions. An ethanol extract of Brazilian green propolis (EEBGP) contains prenylated phenylpropanoids and flavonoids and has antioxidative and anti-inflammatory effects. Acetaminophen (N-acetyl-p-aminophenol; APAP) is a typical hepatotoxic drug, and APAP-treated rats are widely used as a model of drug-induced liver injury. Oxidative stress and inflammatory reactions cause APAP-induced hepatocellular necrosis and are also related to expansion of the lesion. In the present study, we investigated the preventive effects of EEBGP on APAP-induced hepatocellular necrosis in rats and the protective mechanism including the expression of antioxidative enzyme genes and inflammation-related genes. A histological analysis revealed that administration 0.3% EEBGP in the diet for seven days reduced centrilobular hepatocellular necrosis with inflammatory cell infiltration induced by oral administration of APAP (800 mg/kg) and significantly reduced the area of necrosis. EEBGP administration did not significantly change the mRNA expression levels of antioxidant enzyme genes in the liver of APAP-treated rats but decreased the mRNA expression of cytokines including Il10 and Il1b, with a significant difference in Il10 expression. In addition, the decrease in the mRNA levels of the Il1b and Il10 genes significantly correlated with the decrease in the percentage of hepatocellular necrosis. These findings suggest that EEBGP could suppress APAP-induced hepatocellular necrosis by modulating cytokine expression.

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Section: Discussionmentioning

confidence: 98%

Section: Introductionmentioning

confidence: 99%

Brazilian green propolis suppresses acetaminophen-induced hepatocellular necrosis by modulating inflammation-related factors in rats

et al. 2018

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“…The expression levels of mRNA were quantified using RT-qPCR according to our previously described methods ( 14 ). The animals were acclimated for 5–7 days prior to a pre-dose blood draw.…”

Section: Methodsmentioning

confidence: 99%

“…Indeed, animals overexpressing plasma GPx have strong resistance to APAP-induced hepatotoxicity ( 13 ). We have recently shown in mice that, among isozymes of GPx, the degree of APAP-induced hepatotoxicity depends on the mRNA expression levels of GPx3 in the blood ( 14 ). This finding therefore raises the question as to whether the gender difference in the GPx3 level contributes to the difference in APAP-induced hepatotoxicity between genders.…”

Section: Introductionmentioning

confidence: 99%

Glutathione peroxidase 3 is a protective factor against acetaminophen-induced hepatotoxicity in vivo and in vitro

Kanno

Tomizawa

Yomogida

et al. 2017

International Journal of Molecular Medicine

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Acetaminophen (APAP) is a widely available antipyretic and analgesic; however, overdose of the drug inflicts severe damage to the liver. It is well established that the hepatotoxicity of APAP is initiated by formation of a reactive metabolite, N-acetyl-p-benzoquinone imine (NAPQI), which can be detoxified by conjugation with reduced glutathione (GSH), a typical antioxidant. We recently found that the blood mRNA expression level of glutathione peroxidase 3 (Gpx3), which catalyzes the oxidation of GSH, is associated with the extent of APAP-induced hepatotoxicity in mice. The present study was carried out to determine the in vivo and in vitro role of GPx3 in APAP-induced hepatotoxicity. In in vivo experiments, oral administration of APAP to mice induced liver injury. Such liver injury was greater in males than in females, although no gender difference in the plasma concentration of APAP was found. Female mice had a 2-fold higher expression of Gpx3 mRNA and higher plasma GPx activity than male mice. 17β-estradiol, a major female hormone, decreased APAP-induced hepatotoxicity and increased both the expression of blood Gpx3 mRNA and plasma GPx activity, suggesting that the cytoprotective action of this hormone is mediated by the increase in GPx3. To further clarify the role of GPx3 in APAP-induced hepatotoxicity, we evaluated the effect of a change in cellular GPx3 expression resulting from transfection of either siRNA-GPx3 or a GPx3 expression vector on NAPQI-induced cellular injury (as assessed by a tetrazolium assay) in in vitro experiments using heterogeneous cultured human cell lines (Huh-7 or K562). NAPQI-induced cell death was reduced by increased GPx3 and was enhanced by decreased GPx3. These results suggest that GPx3 is an important factor for inhibition of APAP-induced hepatotoxicity both in vivo and in vitro. To our knowledge, this is the first report to show a hepatoprotective role of cellular GPx3 against APAP-induced liver damage.

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“…Paracetamol (PC) is a commonly used as analgesic and antipyretic drug [1]. It is safe at therapeutic levels, but at high doses it can lead to undesirable side effects such as hepatotoxicity and nephrotoxicity [2].…”

Section: Introductionmentioning

confidence: 99%

Chrysin Protects Rat Kidney from Paracetamol-Induced Oxidative Stress, Inflammation, Apoptosis, and Autophagy: A Multi-Biomarker Approach

et al. 2017

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Paracetamol (PC) is a safe analgesic and antipyretic drug at therapeutic doses, and it is widely used in clinics. However, at high doses, it can induce hepatotoxicity and nephrotoxicity. Chrysin (CR) is a natural flavonoid that has biological activities that include being an antioxidant, an anti-inflammatory, and an anti-cancer agent. The main objective of this study was to investigate the efficacy of CR against PC-induced nephrotoxicity in rats. CR was given orally via feeding needle to male Sprague Dawley rats as a single daily dose of 25 or 50 mg/kg for six days. PC was administered orally via feeding needle as a single dose on the sixth day. PC caused significant glutathione depletion, lipid peroxidation, increased serum toxicity markers (serum urea and creatinine), and reductions in activities of antioxidant enzymes (superoxide dismutase — SOD, catalase — CAT, and glutathione peroxidase — GPx). The renal protective effect of CR was associated with decreasing the regulation of serum renal toxicity markers and increasing the regulation of antioxidant enzyme activities. Additionally, PC led to significant increases in the levels of inflammatory markers including tumour necrosis factor-alpha (TNF-α), interleukin-1β (IL-1β) and interleukin-33 (IL-33). Furthermore, PC induced apoptotic tissue damage by increasing cysteine aspartate-specific protease-3 (caspase-3) activity and autophagic tissue damage by increasing the expression of light chain 3B (LC3B). CR therapy significantly decreased these values in rats. This study demonstrated that CR has antioxidant, anti-apoptotic, anti-inflammatory and anti-autophagic effects on PC-induced kidney toxicity in rats.

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Detecting mRNA Predictors of Acetaminophen-Induced Hepatotoxicity in Mouse Blood Using Quantitative Real-Time PCR

Cited by 7 publications

References 33 publications

Brazilian green propolis suppresses acetaminophen-induced hepatocellular necrosis by modulating inflammation-related factors in rats

Brazilian green propolis suppresses acetaminophen-induced hepatocellular necrosis by modulating inflammation-related factors in rats

Glutathione peroxidase 3 is a protective factor against acetaminophen-induced hepatotoxicity in vivo and in vitro

Chrysin Protects Rat Kidney from Paracetamol-Induced Oxidative Stress, Inflammation, Apoptosis, and Autophagy: A Multi-Biomarker Approach

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