Mechanisms of the inhibitory effect of ethanol on acetaminophen hepatotoxicity are controversial. The authors studied the effects of ethanol and acetaldehyde, and oxidative metabolite of ethanol, on NADHP-dependent acetaminophen-glutathione conjugate production in liver microsomes. Ethanol at concentrations as low as 2mM prevented the ...

3,4-Methylenedioxyphenol (sesamol) is effective against acetaminophen-induced liver injury in rats. Whether sesamol's anti-hepatotoxic effect is comparable to that of N-acetylcysteine has never been studied. We investigated the anti-hepatotoxic effects of sesamol and N-acetylcysteine on ...

We have identified the xenobiotic receptor CAR (constitutive androstane receptor) as a key regulator of acetaminophen metabolism and hepatotoxicity. Known CAR activators as well as high doses of acetaminophen induced expression of three acetaminophen-metabolizing enzymes in wild-type but not in CAR-...

Although it is a commonly used analgesic, acetaminophen can be highly hepatotoxic. This study seeks to further investigate the mechanisms involved in acetaminophen-induced hepatotoxicity, as well as the role of CXCR2 receptor/ligand interactions in the liver�s response to and recovery from ...

The dose- and time-related hepatotoxic effects of acetaminophen were investigated in rats using biochemical parameters as indices of hepatotoxicity supplemented by the histopathological examination of the livers. The acute or subacute (twice daily for 7 days) administration of 0.25 g/kg acetaminophen did not ...

A 44 year old female, previously on propranolol, phenytoin and phenobarbital, developed hepatotoxicity while on sulindac and acetaminophen containing analgesic. A limited review of hepatotoxicity and drug interactions of sulindac is presented. The possible mechanism of hepatotoxicity and its treatment is suggested. ...

... analysis suggests that 50% are related to drug hepatotoxicity (acetaminophen toxicity in 32%) and Page 5. 5 ... 2 x ULN in Alkaline Phosphate OR >2 ...

... Acetadote, administered intravenously within 8 to 10 hours after ingestion of a potentially hepatotoxic quantity of acetaminophen, is indicated to ...

NON-IMMUNE MECHANISMS OF DILI: LESSONS FROM THE ACETAMINOPHEN MOUSE MODEL Neil Kaplowitz, MD ... Effect of JNK1+2 Knockdown (antisense) on Acetaminophen Toxicity 0 ...

Gender is a factor that influences susceptibility of individuals to drug-induced liver injury in experimental animals and humans. In this study, we investigated the mechanisms underlying resistance of female mice to acetaminophen (APAP)-induced hepatotoxicity. Overnight-fasted male and female CD-1 mice were administered APAP intraperitoneally. A minor ...

It has been reported that dietary polyunsaturated fats (PUFA) increase liver injury in response to ethanol feeding. We tested the hypothesis that diets rich in linoleic acid (18:2n-6) would affect acute liver injury after acetaminophen injection and that protein restriction might exacerbate the liver injury. We examined effects of feeding diets with either 15% (wt/wt) corn oil ...

Considering the well-documented protection of acetylcysteine (AC) in hepatotoxicity related to acetaminophen, we studied the preventive potential of AC against mild hepatotoxicity of CCl4, potentiated with ethyl alcohol (ETH) and the role of tissue glutathione. Rats fed a liquid diet with 30% of energy from ETH, had-intraperitoneal ...

N-Acetylcysteine is the drug of choice for the treatment of an acetaminophen overdose. It is thought to provide cysteine for glutathione synthesis and possibly to form an adduct directly with the toxic metabolite of acetaminophen, N-acetyl-p-benzoquinoneimine. However, these hypothese have not been tested in vivo, and other mechanisms of action such as ...

The effect of the inducible forms of 70 kDa heat shock protein (Hsp70i) on acetaminophen (APAP) hepatotoxicity was assessed in an Hsp70i knockout mouse model. Absence of the Hsp70i protein in liver was verified by monitoring Hsp levels in knockout and control mice after heat stress (41.5 {sup o}C water bath immersion for 30 min). Hsp70i knockout mice were ...

There is considerable evidence that the concentration of reduced gluthione in the liver is an important determinant of susceptibility to acetaminophen-induced hepatotoxicity. The role which different genetically determined levels of hepatic glutathione ma...

... A, a lignan component of Schisandra fruits, on acetaminophen-induced hepatotoxicity in rats. Biochem. Pharmacol. 46:1081� ... ...

Research article Validation of ICD-9-CM/ICD-10 coding algorithms for the identification of patients with acetaminophen overdose and hepatotoxicity using administrative data

Context. The risk of hepatotoxicity secondary to acute acetaminophen overdose is related to serum acetaminophen concentration and lag time from ingestion to N-acetylcysteine (NAC) therapy. Psi (Greek letter ?) is a toxicokinetic parameter that takes the acetaminophen level at 4 h post-ingestion ([APAP](4 h)) and ...

Hypoxia-inducible factor-1? (HIF-1?) is a critical transcription factor that controls oxygen homeostasis in response to hypoxia, inflammation, and oxidative stress. HIF has been implicated in the pathogenesis of liver injury in which these events play a role, including acetaminophen (APAP) overdose, which is the leading cause of acute liver failure in the United States. APAP ...

The mode of hepatorenal toxicity of acetaminophen (AAP) was compared between fructose-induced hyper-triglyceridemic and normal rats. The hypertriglyceridemic and normal rats received a single dose of AAP (0, 750 and 900 mg/kg ip) at week 5 of fructose-treatment. At 24 hrs after AAP-dosing, they were sacrificed and examined blood biochemically and ...

For over 50 years, acetaminophen (paracetamol) has been a staple in industrialized and non-industrialized countries for the treatment of pain and fever. Although its precise mechanisms of action are not known, the drug generates dose-dependent reduction in circulating prostaglandins, inhibits myeloperoxidase and the oxidation of lipoproteins, and appears to confer ...

... toxic agents such as acetaminophen, the calcium lonophore A23187, or ... acetaminophen is dependent upon extensive metabolic activation, is ...

Precision-cut liver slices (PCLS) preserve the tissular organization of the organ and represent an in vitro model closer to in vivo conditions than hepatocytes cultures. As this may be an interesting tool not only for the investigation of hepatotoxic and protective effects but also for bioguided fractionations schemes, the usefulness of PCLS was compared ...

Acetaminophen (APAP) overdose is the most frequent cause of adult acute liver failure. Susceptibility or resistance to APAP toxicity is most likely accounted for by the interplay of several factors. One factor important in multiple different chronic liver diseases that may play a role in APAP toxicity is elevated hepatic iron. Hereditary hemochromatosis is traditionally ...

Groups of male Swiss-Webster mice were gavaged with acetaminophen (APAP), APAP + ascorbyl stearate (AS), or APAP + ascorbyl palmitate (AP) at a dose of 600 mg/kg for each chemical. APAP alone caused a significant increase in liver weight/body weight ratio and hepatic glutathione (GSH) depletion. Co-administration of the ascorbate esters AP or AS with APAP prevented an increase ...

Aim:Acetaminophen (APAP) can change to toxic metabolites at high dose; if these metabolites are in high amounts, the body will be unable to neutralize them, and several tissues including liver will be damaged. In the present study, the effect of vanadium was compared with deferoxamine on hepatotoxicity and also kidney function during ...

Medicinal herbs have been used for centuries in an attempt to overcome hepatic dysfunctions emanating from ingestion of hepatotoxic substances. However, the vast majority of information concerning their use is anecdotal. Well-performed animal studies would lend credence to the concept that some medicinal herbs may prevent or, at least ameliorate, hepatic dysfunction arising ...

Inhibition of the cytochrome P-450-dependent formation of the acetaminophen-reactive metabolite was investigated as a possible mechanism for cysteamine protection against acetaminophen hepatotoxicity. Studies in isolated hamster hepatocytes indicated that cysteamine competitively inhibited the cytochrome P-450 enzyme system as ...

A reactive metabolite of acetaminophen is hepatotoxic in humans when the drug is ingested in large overdoses. The ability of the human fetal and adult liver to oxidize acetaminophen by trapping the potentially toxic metabolite as a glutathione conjugate has been measured. Oxidation by fetal liver was approximately ten times slower than ...

Acetaminophen/paracetamol-induced liver failure-which is induced by the binding of reactive metabolites to mitochondrial proteins and their disruption-is exacerbated by fasting. As fasting promotes SIRT3-mediated mitochondrial-protein deacetylation and acetaminophen metabolites bind to lysine residues, we investigated whether deacetylation predisposes mice ...

3'-Hydroxyacetaminophen, a catechol metabolite of N-acetyl-p-aminophenol (acetaminophen) and N-acetyl-m-aminophenol (a structural analogue of acetaminophen and considered as a possible alternative because it is not hepatotoxic), is enzymatically synthesized for the first time using mushroom tyrosinase. Although reported to be weakly ...

; College of Pharmacy The Role of Aging in the Formation of Acetaminophen Protein Adducts This project developed in our laboratory for the measurement of a biomarker of acetaminophen (APAP) hepatotoxicity old mice. Acetaminophen, a commonly used antipyretic and analgesic, is safe in therapeutic doses

The transcription factor NFE2-related factor 2 (Nrf2) mediates detoxification and antioxidant gene transcription following electrophile exposure and oxidative stress. Mice deficient in Nrf2 (Nrf2-null) are highly susceptible to acetaminophen (APAP) hepatotoxicity and exhibit lower basal and inducible expression of cytoprotective genes, including NADPH ...

Acetaminophen (APAP) with or without ascorbyl stearate (AS) or ascorbyl palmitate (AP) was administered by gavage to male Swiss-Webster mice at a dose of 600 mg/kg for each chemical. The biochemical markers of hepatotoxicity, serum transaminases (serum glutamate pyruvate transaminase [SGPT], serum glutamate oxaloacetic transaminase [SGOT]) and serum ...

Acetaminophen (APAP) is safe at therapeutic levels but causes hepatotoxicity via N-acetyl-p-benzoquinone imine-induced oxidative stress upon overdose. To determine the effect of human (h) pregnane X receptor (PXR) activation and CYP3A4 induction on APAP-induced hepatotoxicity, mice humanized for PXR and CYP3A4 (TgCYP3A4/hPXR) were ...

... modifier subunit deficiency and gender as determinants of acetaminophen-induced hepatotoxicity in mice. Toxicol. Sci 99:628� ... ...

... Gonzalez. Role of CYP2E1 in the hepatotoxicity of acetaminophen. J Biol Chem 1996. 271:12063�12067. CrossRef, ... ...

The frequent use of rodent hepatic in vitro systems in pharmacological and toxicological investigations challenges extrapolation of in vitro results to the situation in vivo and interspecies extrapolation from rodents to humans. The toxicogenomics approach may aid in evaluating relevance of these model systems for human risk assessment by direct comparison of toxicant-induced gene expression ...

An approach previously developed for studying the effects of toxic mixtures on whole organism performances (i.e., growth, mortality) was evaluated to determine its applicability and limitations at the organ system level. The approach was tested by quantifying the hepatotoxic effects of carbon tetrachloride (CCl/sub 4/), monochlorobenzene (MCB), ...

Caveolin-1 (Cav-1) is a membrane scaffolding protein, which functions to regulate intracellular compartmentalization of various signaling molecules. In the present studies, transgenic mice with a targeted disruption of the Cav-1 gene (Cav-1{sup -/-}) were used to assess the role of Cav-1 in acetaminophen-induced hepatotoxicity. Treatment of wild-type mice ...

Caveolin-1 (Cav-1) is a membrane scaffolding protein which functions to regulate intracellular compartmentalization of various signaling molecules. In the present studies, transgenic mice with a targeted disruption of the Cav-1 gene (Cav-1^?/?) were used to assess the role of Cav-1 in acetaminophen-induced hepatotoxicity. Treatment of ...

ABSTRACT Acetaminophen injection is an antipyretic and analgesic agent recently marketed in the United States as Ofirmev. Five published trials directly compare acetaminophen injection to drugs available in the United States. For management of pain in adults, acetaminophen injection was at least as effective as ...

In vivo and in vitro covalent binding of foreign chemicals to tissue macromolecules via metabolic activation is described, using the analgesic acetaminophen as an example. Acetaminophen is metabolized through a variety of pathways. The arylating metabolite is formed by a cytochrome P-450 dependent N-hydroxylation process. The resulting hydroxamic acid is ...

BACKGROUND: The acetaminophen risk analysis nomogram is used to predict hepatotoxicity risk in acute acetaminophen overdose based on a single plasma acetaminophen concentration (PAC) measured between 4 and 24 h after ingestion. There are case reports of patients with acute overdoses of ...

Paracetamol (acetaminophen, PCM) is widely used as an over-the-counter analgesic and antipyretic drug. Intake of a large dose of PCM may result in severe hepatic necrosis. Oxidative stress mediated by oxidative capacities of the PCM metabolite (N-acetyl-p-benzoquinoneimine (NAPQI), is considered as the main cause of hepatotoxicity of PCM. This work ...

BACKGROUND& AIMS: Nuclear receptors such as pregnane X receptor and constitutive androstane receptor (CAR) are important regulators of drug-metabolizing systems such as P450s enzymes and modulate xenobiotic metabolism as well as hepatocellular proliferation. Binding of CAR to NR response elements alone is not sufficient to activate gene expression. Here we investigate the role of steroid ...

This study investigated the possible protective effects and mechanism of rhein on Acetaminophen (APAP)-induced hepatotoxicity and nephrotoxicity in rats. Treatment of rats with APAP resulted in severe liver and kidney injuries, as demonstrated by drastic elevation of serum glutamate-pyruvate transaminase (GPT), glutamate-oxaloacetic transaminase (GOT), ...

Neutrophils are recruited into the liver after acetaminophen (AAP) overdose but the pathophysiological relevance of this acute inflammatory response remains unclear. To address this question, we compared the time course of liver injury, hepatic neutrophil accumulation and inflammatory gene mRNA expression for up to 24 h after treatment with 300 mg/kg AAP ...

We previously reported that liver natural killer (NK) and NKT cells play a critical role in mouse model of acetaminophen (APAP)-induced liver injury by producing interferon gamma (IFN-gamma) and modulating chemokine production and subsequent recruitment of neutrophils into the liver. In this report, we examined the role of neutrophils in the progression of APAP ...

The pregnane X receptor (PXR) is a master regulator of xenobiotic clearance and is implicated in deleterious drug interactions (e.g., acetaminophen hepatotoxicity) and cancer drug resistance. However, small-molecule targeting of this receptor has been difficult; to date, directed synthesis of a relatively specific PXR inhibitor has remained elusive. Here ...

5-Oxoproline (5-OP; pyroglutamate) is an intermediate in the biosynthesis of the endogenous tripeptide glutathione and has been seen to be elevated in the biofluids and tissues of rats following the administration of glutathione-depleting hepatotoxic xenobiotics such as acetaminophen (paracetamol), bromobenzene and ethionine. As 5-OP is a potential ...

The widely used analgesic-antipyretic drug acetaminophen (APAP) is known to cause serious liver necrosis at high doses in man and experimental animals. For studies of toxic processes, 1H NMR spectroscopy of biofluids allows monitoring of endogenous metabolite profiles that alter characteristically in response to changes in physiological status. Herein, a 1H NMR metabolomics ...

... Abstract : The comparative hepatotoxicities of perfluorooctanoic acid (PFOA), perfluorodecanoic acid (PFDA) and the tri-and tetra-oligomers of ...

Fructose-induced hypertriglyceridemic rats become resistant to hepatotoxicity and susceptible to nephrotoxicity of acetaminophen (APAP), as compared with normal ones. The present study was designed to test the hypothesis that alterations in the distribution of APAP and in the intrinsic susceptibility to toxicants are responsible for ...

Fructose-induced hypertriglyceridemic rats are resistant to hepatoxicity and susceptible to nephrotoxicity of acetaminophen (APAP) as compared with normal ones. The present studied were designed to evaluate how fructose-treatment affects the developmental mode of hepatorenal toxicity of APAP. First, following fructose-pretreatment for various durations (1 ...

Severe acute liver injury due to accidental or intentional acetaminophen overdose presents a major clinical dilemma often requiring liver transplantation. In the present study, liver regeneration after profound liver injury in mice challenged with acetaminophen was facilitated by the exogenous addition of ELR-containing CXC chemokines such as macrophage ...

Liver transplantation (LT) may be life-saving in severe acute liver failure (ALF). The aim of this study was to compare the utilization of LT in acetaminophen and non-acetaminophen ALF. Between 1992 and 2006, 469 patients with ALF were admitted, and 104 underwent LT. Acetaminophen was the most common etiology, but ...

Hepatocytes have been used for in vitro hepatotoxicity assays because of their ability to sustain intact liver-specific functions. Here, we demonstrate a hepatotoxicity assay system using primary human hepatocytes trapped in microholes of a microfluidic device, providing a microscale in vivo liver-like environment. We performed microfluidic ...

The low incidence of idiosyncratic drug-induced liver injury (DILI), together with the lack of a reliable diagnostic biomarker and robust preclinical and in vitro toxicology test systems for the condition have limited our ability to define the mechanisms of DILI. A notable exception is acetaminophen hepatotoxicity, which is associated with the formation of ...

Certain disease conditions can modify drug-induced toxicities, which, in turn, may cause a medication-related health crisis. Therefore, preclinical investigations into the alterations in drug-induced toxicities using appropriate disease animal models are very important. This paper reviews the reported data related to the effects of diabetes and hypertriglyceridemia, common lifestyle-related ...

Acetaminophen (APAP) hepatotoxicity is the main cause of acute liver failure in humans. Although mitochondrial oxidant stress and induction of the mitochondrial permeability transition (MPT) have been implicated in APAP-induced hepatotoxicity, the link between these events is unclear. To investigate this, this study evaluated APAP ...

The methanol extract of the leaves of Centaurium erythraea L. (Gentianaceae) was evaluated for hepatoprotective activity against acetaminophen-induced liver toxicity in rats. An oral dose of 300 mg/kg/day for 6 days or a single dose of 900 mg/kg for 1 day exhibited a significant protective effect by lowering serum glutamate oxaloacetate transaminase (SGOT), glutamate pyruvate ...