Oxidative stress by acute acetaminophen administration in mouse liver

doi:10.1016/0891-5849(95)00023-Q

Free Radical Biology and Medicine

Volume 19, Issue 3, September 1995, Pages 303-310

https://doi.org/10.1016/0891-5849(95)00023-Q Get rights and content

Abstract

Acetaminophen was given to mice at a single dose of 375 mg/kg. In situ liver chemiluminescence, H₂O₂ steady-state concentration, and the liver concentrations of total and oxidized glutathione were measured 15, 30, and 60 min after acetaminophen administration. Increases of 145% and 72% in spontaneous chemiluminescence and H₂O₂ concentration were observed 15 min after the injection, respectively. Total glutathione was decreased by acetaminophen administration at all the times studied. The maximal decrease, 83%, was found 60 min postinjection. The ratio GSH/GSSG was found significantly decreased at all the times studied. Microsomal superoxide production was increased by 2.4-fold by addition of acetaminophen. The activities of the antioxidant enzymes superoxide dismutase, catalase, and glutathione peroxidase were determined. Catalase was slightly inhibited (30%) 15 min after acetaminophen administration. No significant changes were found in superoxide dismutase activity. Se and non-Se glutathione peroxidase activities were decreased by 40% and 53% respectively, 15 min after acetaminophen administration. The decrease in catalase and glutathione peroxidase would result in an increased steady state level of H₂0₂ and hydroperoxides, contributing to cell injury. Damaged hepatocytes were observed, and severe lesions and necrosis appeared 60 min after acetaminophen administration. Our results indicate the occurrence of oxidative stress as a possible mechanism for acetaminophen-induced hepatotoxicity.

References (33)

S. Orrenius et al.
The multiple roles of glutathione in drug metabolism
TIPS
(1984)
J.M. Tredger et al.
Effects of sulfur-containing compounds on paracetamol activation and covalent binding in a mouse hepatic microsomal system
Toxicol. Lett.
(1980)
M. Moore et al.
The toxicity of acetaminophen and N-acetyl-p-benzoquinone imine in isolated hepatocytes is associated with thiol depletion and increased cytosolic Ca²⁺
J. Biol. Chem.
(1985)
S.D. Ray et al.
Early loss of large genomic DNA in vivo with accumulation of calcium in the nucleus during acetaminophen-induced liver injury
Toxicol. Appl. Pharmacol.
(1990)
W. Shen et al.
Acetaminophen-induced cytotoxicity in cultured mouse hepatocytes: Effects of Ca²⁺-endonuclease, DNA repair, and glutathione depletion inhibitors on DNA fragmentation and cell death
Toxicol. Appl. Pharmacol.
(1992)
T.P.M. Akerboom et al.
Assay of glutathione, glutathione disulfide, and glutathione mixed disulfides in biological samples
Meth. Enzymol.
(1981)
A. Boveris
Determination of the production of superoxide radicals and hydrogen peroxide in mitochondria
Meth. Enzymol.
(1984)
H.P. Misra et al.
The role of superoxide anion in the autoxidation of epinephrine and a simple assay for superoxide dismutase
J. Biol. Chem.
(1972)
A. Boveris et al.
Increased chemiluminescence and superoxide production in the liver of chronically ethanol-treated rats
Arch. Biochem. Biophys.
(1983)
A. Boveris et al.
Increased liver chemiluminescence in tumor-bearing mice
Free Radic. Biol. Med.
(1985)

S. Llesuy et al.

Hepatotoxicity of mitoxantrone and doxorubicin

Toxicology

(1990)

C. Giulivi et al.

Superoxide-mediated lung damage in paraquat poisoning and hyperbaric oxygen exposure: Site-specific inhibition of phospholipase A₂

Free Radic. Biol. Med.

(1995)

S. Llesuy et al.

Oxidative stress in muscle and liver of rats with septic syndrome

Free Radic. Biol. Med.

(1994)

E. Cadenas et al.

Low-level chemiluminescence as an indicator of singlet molecular oxygen in biological systems

Meth. Enzymol.

(1984)

E. Cadenas et al.

Electronically excited state formation

S. Uhlig et al.

The physiological consequences of glutathione variations

Life Sciences

(1992)

Cited by (162)

Investigation on toxicity and mechanism to Daphnia magna for 14 disinfection by-products: Enzyme activity and molecular docking
2023, Science of the Total Environment
Exposure to disinfection by-products (DBPs) has been found to induce a range of toxic effects in aquatic organism. Previous studies have consistently demonstrated that a majority of DBPs have the ability to induce in vivo toxicity in aquatic organisms. However, the impact of DBPs on the metabolic processes of Daphnia magna (D. magna) and the underlying molecular toxicity mechanisms are still not well understood. Therefore, we investigated the effects of 14 DBPs on two oxidative stress enzymes and malondialdehyde (MDA) levels in D. magna. Additionally, we employed molecular docking to simulate the toxicity of DBPs to D. magna at the molecular level. This comprehensive analysis allowed us to gain further insights into the toxicity of DBPs on D. magna. The results showed that among the aliphatic DBPs, the more bromine substituents, the lower the toxicity effect, and it's opposite in the aromatic DBPs. In the detection of oxidative stress level, catalase (CAT) enzyme and superoxide dismutase (SOD) enzyme in D. magna under compound stress showed a low increase and decrease with the increase of concentration. The level of MDA showed a positive correlation with the concentration. In the last, molecular docking simulations have shown promise in predicting the toxicity of DBPs and providing insights into their toxic effects to a certain extent, and the docking situation of P53 is slightly different. Hence, it is imperative to further regulate the presence of aromatic DBPs due to their pronounced toxic effects on D. magna, and these simulations can be complemented with actual experiments to enhance our understanding of the toxicity mechanisms of DBPs.
Urinary concentrations of acetaminophen in young children in central and south China: Repeated measurements and associations with 8-hydroxy-guanosine and 8-hydroxy-2′-deoxyguanosine
2021, Science of the Total Environment
Citation Excerpt :
Moreover, urinary concentrations of AAP (unintentional exposure via diet) were reported to be associated with longer time to pregnancy (median: 26.6 and 13.2 ng/mL for females and males, respectively) (Smarr et al., 2016) and lower semen quality (15.5 ng/mL [interquartile range 5.44, 73.5]) (Smarr et al., 2017) in males. AAP has been known to induce mitochondria dysfunction (Jaeschke et al., 2012; Umbaugh et al., 2021), oxidative stress (Lores Arnaiz et al., 1995; Wang et al., 2017), and inflammatory responses (Jaeschke and Ramachandran, 2020) in the pathogenesis of AAP hepatotoxicity (Shan et al., 2018). Various studies in cells and animals such as human beings, rabbits, rats, and mice, have identified that oxidative stress plays a critical role in the toxic effects induced by AAP (Wang et al., 2017).
Acetaminophen (AAP) is the most widely used over-the-counter analgesic in the world; it is also a metabolite of industrial chemical aniline. It may predispose individuals to oxidative stress. However, the exposure profile of AAP in the general population in China and the associations between AAP and oxidative stress biomarkers have scarcely been investigated. In this study, we determined the urinary concentrations of AAP and evaluated its associations with 8-hydroxy-guanosine (8-OHG) and 8-hydroxy-2′-deoxyguanosine (8-OHdG), the most widely used biomarkers of nucleoside oxidation affecting RNA and DNA, in 393 urine samples collected from 131 healthy children (0–6.6 y) on three consecutive days from Wuhan, central China, and Shenzhen, south China. AAP was found in all urine samples, suggesting that exposure to AAP was ubiquitous in young children in central and south China. The median concentration of specific gravity (SG)-adjusted AAP was 9.21 ng/mL (range: 1.11–1 453 ng/mL). Good inter-day reproducibility was observed for SG-adjusted AAP concentrations (intraclass correlation coefficient, 0.75). The SG-adjusted urinary 8-OHdG and 8-OHG concentrations were positively correlated with AAP (β = 0.08; 95% confidence interval [95% CI]: 0.02–0.13, and β = 0.10; 95% CI: 0.04–0.15, respectively). The data indicated that AAP exposure might be associated with oxidative DNA and RNA damage in the general population with unintentional exposure. To our knowledge, this is the first report of AAP exposure in young healthy children in central and south China. This is also the first study to evaluate the inter-day variations in urinary AAP concentrations and to explore the associations between AAP exposure and oxidative stress biomarkers in the general population.
Transcriptomic analysis across liver diseases reveals disease-modulating activation of constitutive androstane receptor in cholestasis
2020, JHEP Reports
Citation Excerpt :
Furthermore, even control animals exhibited a decrease in the concentrations of reduced GSH, albeit not reaching significance after androstanol treatment. Recently, bile acids, as well as Gstp1/2 deletion, were shown to cause resistance to APAP toxicity.33–36 Thus, bile acids and CAR-driven mechanisms may protect the DKO mice from APAP toxicity.
Liver diseases are caused by many factors, such as genetics, nutrition, and viruses. Therefore, it is important to delineate transcriptomic changes that occur in various liver diseases.
We performed high-throughput sequencing of mouse livers with diverse types of injuries, including cholestasis, diet-induced steatosis, and partial hepatectomy. Comparative analysis of liver transcriptome from mice and human samples of viral infections (HBV and HCV), alcoholic hepatitis (AH), non-alcoholic steatohepatitis (NASH), and biliary atresia revealed distinct and overlapping gene profiles associated with liver diseases. We hypothesised that discrete molecular signatures could be utilised to assess therapeutic outcomes. We focused on cholestasis to test and validate the hypothesis using pharmacological approaches.
Here, we report significant overlap in the expression of inflammatory and proliferation-related genes across liver diseases. However, cholestatic livers were unique and displayed robust induction of genes involved in drug metabolism. Consistently, we found that constitutive androstane receptor (CAR) activation is crucial for the induction of the drug metabolic gene programme in cholestasis. When challenged, cholestatic mice were protected against zoxazolamine-induced paralysis and acetaminophen-induced hepatotoxicity. These protective effects were diminished upon inhibition of CAR activity. Further, drug metabolic genes were also induced in the livers from a subset of biliary atresia patients, but not in HBV and HCV infections, AH, or NASH. We also found a higher expression of CYP2B6, a CAR target, in the livers of biliary atresia patients, underscoring the clinical importance of our findings.
Comparative transcriptome analysis of different liver disorders revealed specific induction of phase I and II metabolic genes in cholestasis. Our results demonstrate that CAR activation may lead to variations in drug metabolism and clinical outcomes in biliary atresia.
Transcriptomic analysis of diverse liver diseases revealed alterations in common and distinct pathways. Specifically, in cholestasis, we found that detoxification genes and their activity are increased. Thus, cholestatic patients may have an unintended consequence on drug metabolism and not only have a beneficial effect against liver toxicity, but also may require adjustments to their therapeutic dosage.
Antioxidative and neurotoxicity effects of acute and chronic exposure of the estuarine polychaete Hediste diversicolor to paracetamol
2020, Environmental Toxicology and Pharmacology
The presence of anthropogenic drugs in the aquatic ecosystems is a reality nowadays, and a large number of studies have been reporting their putative toxic effects on wildlife. However, the majority of the studies published so far uses standard organisms, whose probability of becoming in contact with drugs in real scenarios of contamination is at least, low. The use of autochthonous organisms in ecotoxicity testing is thus mandatory, and the present study aimed to assess the feasibility of assessing oxidative based stress responses (enzymatic defenses, such as catalase, glutathione-s-transferases, and lipid peroxidation; neurotoxicity as an indirect outcome of oxidizing conditions) on a polychaete species, Hediste diversicolor, after being acutely and chronically exposed to the widely employed drug paracetamol. H. diversicolor showed to be responsive to paracetamol exposure. Data obtained after acute exposure to paracetamol showed that no antioxidant adaptive response was established, but cholinesterasic activity was enhanced. On the contrary, long term exposure of H. diversicolor individuals to paracetamol resulted in clear pro-oxidative effects, with catalase and cholinesterase inhibition, and a significant reduction in the levels of lipoperoxidation. Considering that some of the tested levels (especially those of the chronic test) were already reported in the wild, the here-obtained results are of high environmental significance. In addition, chronic exposure regime yielded more significant results, with important modification of more parameters, suggesting that realistic conditions of exposure are more suited for an integrated assessment of toxicity of drugs in aquatic organisms.
Protective effects of p-coumaric acid against acetaminophen-induced hepatotoxicity in mice
2018, Food and Chemical Toxicology
Acetaminophen (N-acetyl-p-aminophenol, AAP) is an effective analgesic and antipyretic drug with minimal toxicity when used at therapeutic doses. However, AAP overdose is the most common cause of drug-induced acute liver failure and one of the main causes of morbidity and mortality. p-Coumaric acid (PCA) is the most abundant isomer of hydroxycinnamic acid in nature, and it can be widely found in fruits, vegetables, and plants products. PCA has strong antioxidant activity and exhibits protective effects in numerous disease models associated with reactive oxygen species (ROS) generation. In this study, we investigated the protective effects of PCA on AAP-induced hepatotoxicity and the underlying mechanisms using an in vivo model. We found that PCA ameliorates AAP-induced hepatotoxicity as well as the reduced serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST) activity. Furthermore, we observed that PCA suppressed hepatic apoptosis via ROS-mediated DNA damage responses and inflammation by modulating the mitogen-activated protein kinase (MAPK) signaling axis in an ROS-dependent manner. These findings indicate that the administration of PCA protects against AAP-induced hepatotoxicity, suggesting it could be a novel therapeutic strategy for AAP-induced liver injury.
Sestrin2 protects against acetaminophen-induced liver injury
2017, Chemico-Biological Interactions
Acetaminophen (APAP) overdose accounts for half of the cases of acute liver failure worldwide. We previously reported that Sestrin2 (Sesn2) protects against d-galactosamine/lipopolysaccharide-induced acute fulminant liver failure. In this study, we demonstrated that Sesn2 protects APAP-induced liver injury in mice, using a recombinant adenovirus encoding Sesn2 (Ad-Sesn2). First, we found that treatment of mice with toxic levels of APAP significantly reduced Sesn2 expression. Tail-vein injection with Ad-Sesn2 inhibited APAP-induced serum alanine aminotransferase and aspartate aminotransferase levels and markedly reduced hepatocyte degeneration and inflammatory cell infiltration. Additionally, APAP-induced glutathione depletion and reactive oxygen species generation were inhibited by Ad-Sesn2 treatment. Consistently, hepatic inflammatory gene expression and proinflammatory cytokine levels were also inhibited in Sesn2-infected mice, and we observed reduced APAP-mediated apoptotic signaling by terminal transferase-mediated dUTP nick-end labeling staining of the hepatic tissue. At a high dose of APAP, the mortality rate of Ad-Sesn2-infected mice was significantly lower than that of control mice. Furthermore, Sesn2 prevented APAP-induced damage through suppression of downstream mitogen-activated protein kinase pathway activation. Therefore, Sesn2 exerted a protective effect against APAP-induced acute liver damage by inhibiting oxidative stress and proinflammatory signaling.

View all citing articles on Scopus

View full text

Original contributionOxidative stress by acute acetaminophen administration in mouse liver

Abstract

TIPS

Toxicol. Lett.

J. Biol. Chem.

Toxicol. Appl. Pharmacol.

Toxicol. Appl. Pharmacol.

Meth. Enzymol.

Meth. Enzymol.

J. Biol. Chem.

Arch. Biochem. Biophys.

Free Radic. Biol. Med.

Toxicology

Free Radic. Biol. Med.

Free Radic. Biol. Med.

Meth. Enzymol.

Life Sciences

Original contribution
Oxidative stress by acute acetaminophen administration in mouse liver