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PubMed1994

Association of acetaminophen hepatotoxicity with fasting and ethanol use.

OBJECTIVES: To evaluate the association of fasting and alcohol use with hepatotoxicity from acetaminophen ingested for therapeutic reasons. DESIGN: Retrospective case series. SETTING: Hospitals of the University of Pittsburgh (Pa) Medical Center. PATIENTS: A total of 126,779 discharge summaries from January 1987 to July 1993 were reviewed using a comprehensive, whole-text-indexed medical database to identify all patients with acetaminophen ingestion and hepatotoxicity. These patients were categorized according to the intended acetaminophen use and dose of acetaminophen ingested. MAIN OUTCOMES MEASURED: The independent variables of chronic alcohol use, recent alcohol use, and recent fasting were determined for all patients. RESULTS: Forty-nine patients with acetaminophen hepatotoxicity (aspartate aminotransferase > 1000 U/L) were identified. Twenty-one patients (43%) ingested acetaminophen for therapeutic purposes. All patients with hepatotoxicity took more than the recommended limit of 4 g/d. Recent fasting was more common than recent alcohol use among those who suffered hepatotoxicity after a dose of 4 to 10 g of acetaminophen per day (P = .02). Recent alcohol use was more common in the group who took more than 10 g/d than in those who took 4 to 10 g/d (P = .004). CONCLUSION: Acetaminophen hepatotoxicity after a dose of 4 to 10 g/d was associated with fasting and less commonly with alcohol use. Patients who developed hepatoxicity after taking acetaminophen doses of greater than 10 g/d for therapeutic purposes were alcohol users. Acetaminophen hepatotoxicity after an overdose appears to be enhanced by fasting in addition to alcohol ingestion.

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PubMed2004

Mitochondrial permeability transition in acetaminophen-induced necrosis and apoptosis of cultured mouse hepatocytes.

Acetaminophen overdose causes massive hepatic failure via mechanisms involving glutathione depletion, oxidative stress, and mitochondrial dysfunction. The ultimate target of acetaminophen causing cell death remains uncertain, and the role of apoptosis in acetaminophen-induced cell killing is still controversial. Our aim was to evaluate the mitochondrial permeability transition (MPT) as a key factor in acetaminophen-induced necrotic and apoptotic killing of primary cultured mouse hepatocytes. After administration of 10 mmol/L acetaminophen, necrotic killing increased to more than 49% and 74%, respectively, after 6 and 16 hours. MPT inhibitors, cyclosporin A (CsA), and NIM811 temporarily decreased necrotic killing after 6 hours to 26%, but cytoprotection was lost after 16 hours. Confocal microscopy revealed mitochondrial depolarization and inner membrane permeabilization approximately 4.5 hours after acetaminophen administration. CsA delayed these changes, indicative of the MPT, to approximately 11 hours after acetaminophen administration. Apoptosis indicated by nuclear changes, terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling, and caspase-3 activation also increased after acetaminophen administration. Fructose (20 mmol/L, an adenosine triphosphate-generating glycolytic substrate) plus glycine (5 mmol/L, a membrane stabilizing amino acid) prevented nearly all necrotic cell killing but paradoxically increased apoptosis from 37% to 59% after 16 hours. In the presence of fructose plus glycine, CsA decreased apoptosis and delayed but did not prevent the MPT. In conclusion, after acetaminophen a CsA-sensitive MPT occurred after 3 to 6 hours followed by a CsA-insensitive MPT 9 to 16 hours after acetaminophen. The MPT then induces ATP depletion-dependent necrosis or caspase-dependent apoptosis as determined, in part, by ATP availability from glycolysis.

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PubMed1998

Role of nitric oxide in acetaminophen-induced hepatotoxicity in the rat.

Acetaminophen is a mild analgesic and antipyretic agent known to cause centrilobular hepatic necrosis at toxic doses. Although this may be due to a direct interaction of reactive acetaminophen metabolites with hepatocyte proteins, recent studies have suggested that cytotoxic mediators produced by parenchymal and nonparenchymal cells also contribute to the pathophysiological process. Nitric oxide is a highly reactive oxidant produced in the liver in response to inflammatory mediators. In the present studies we evaluated the role of nitric oxide in the pathophysiology of acetaminophen-induced liver injury. Treatment of male Long Evans Hooded rats with acetaminophen (1 g/kg) resulted in damage to centrilobular regions of the liver and increases in serum transaminase levels, which were evident within 6 hours of treatment of the animals and reached a maximum at 24 hours. This was correlated with expression of inducible nitric oxide synthase (iNOS) protein in these regions. Hepatocytes isolated from both control and acetaminophen-treated rats were found to readily synthesize nitric oxide in response to inflammatory stimuli. Cells isolated from acetaminophen-treated rats produced more nitric oxide than cells from control animals. Production of nitric oxide by cells from both control and acetaminophen-treated rats was blocked by aminoguanidine, a relatively specific inhibitor of iNOS. Arginine uptake and metabolism studies revealed that the inhibitory effects of aminoguanidine were due predominantly to inhibition of iNOS enzyme activity. Pretreatment of rats with aminoguanidine was found to prevent acetaminophen-induced hepatic necrosis and increases in serum transaminase levels. This was associated with reduced nitric oxide production by hepatocytes. Inhibition of toxicity was not due to alterations in acetaminophen metabolism since aminoguanidine had no effect on hepatocyte cytochrome P4502E1 protein expression or N-acetyl-p-benzoquinone-imine formation. Taken together, these data demonstrate that nitric oxide is an important mediator of acetaminophen-induced hepatotoxicity.

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PubMedDate not supplied

Protective effects of MESNA (2-mercaptoethane sulphonate) against acetaminophen-induced hepatorenal oxidative damage in mice.

Acetaminophen, a widely used analgesic and antipyretic, is known to cause hepatic and renal injury in humans and experimental animals when administered in high doses. It was reported that these toxic effects of acetaminophen are due to oxidative reactions that take place during its metabolism. In this study we aimed to investigate the possible beneficial effect of 2-mercaptoethane sulphonate (MESNA), an antioxidant agent, against acetaminophen toxicity in mice. Balb-c mice were injected i.p. with: vehicle (the control group); a single dose of 150 mg kg(-1) MESNA (MES group); a single dose of 900 mg kg(-1) i.p. acetaminophen (AA4h and AA24h groups); and MESNA, at a dose of 150 mg kg(-1) after acetaminophen injection (AA4h-MES and AA24h-MES groups). The MESNA injection was repeated once more 12 h after the first injection in the AA24h-MES group. Blood urea nitrogen, serum creatinine, alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels in blood and glutathione (GSH) and malondialdehyde (MDA) levels, myeloperoxidase (MPO) activity and collagen contents in liver and kidney tissues were measured. Tissues also were examined microscopically. Blood urea nitrogen and serum creatinine, which were increased significantly (P < 0.001) following acetaminophen treatment were decreased significantly (P < 0.05-0.001) after treatment with MESNA. The ALT and AST levels were also increased significantly (P < 0.001) after acetaminophen treatment but were not reduced with MESNA. Acetaminophen treatment caused a significant (P < 0.05-0.001) decrease in GSH levels whereas MDA levels and MPO activity were increased in both tissues. These changes were reversed by MESNA treatment. Collagen contents of the liver and kidney tissues were increased by acetaminophen treatment (P < 0.001) and reversed back to the control levels with MESNA. Our results imply that acetaminophen causes oxidative damage in hepatic and renal tissues and that MESNA, via its antioxidant effects, protects these tissues. Therefore, its therapeutic role as a 'tissue injury-limiting agent' must be elucidated further in drug-induced oxidative damage.

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PubMed1977

Quantitative determination of phenacetin and its metabolite acetaminophen by GLC-chemical ionization mass spectrometry.

A quantitative GLC-mass spectrometric procedure was developed for the determination of phenacetin and its O-desethyl metabolite, acetaminophen, in human plasma. The assay utilizes selective ion detection to monitor, in a GLC effluent, the MH+ molecular ions of both phenacetin and the methyl derivative of acetaminophen, p-acetanisidine, generated by isobutane chemical ionization. Deuterated analogs of phenacetin and acetaminophen, phenacetin-d3 and acetaminophen-d3, respectively, are added to the plasma before extraction to serve as internal standards. To determine phenacetin and unconjugated acetaminophen, 1.0 ml of plasma is extracted with 5 ml of benzene-dichloroethane (7:3). The extraction solvent is removed, and the residue is methylated with diazomethane. Th solution is again evaporated to dryness, and the residue is reconstituted in ethyl acetate. A portion of this solution is then analyzed by GLC-mass spectrometry, with the mass spectrometer set to monitor m/e 166 (p-acetanisidine), 169 (p-acetanisidine-d3), 180 (phenacetin), and 183 (phenacetin-d3). To determine total acetaminophen, 0.1 ml of plasma is treated with a mixture of beta-glucuronidase and sulfatase, extracted with ethyl acetate, methylated, and analyzed by GLC-mass spectrometry. The procedure has a sensitivity limit of 1 ng of phenacetin/ml and 0.1 mug of acetaminophen/ml. The curves relating the amount of phenacetin and acetaminophen added versus the amount of phenacetin and acetaminophen found for 12 known phenacetin concentrations over the 9.9-246.6-ng/ml range and for 16 known acetaminophen concentrations over the 0.52-13.10-mug/ml range are straight lines with intercepts of nearly zero and with slopes of unity. Analyses of six separate plasma samples, each containing 25 ng of phenacetin/ml and 1.31 mug of acetaminophen/ml, had a precision of +/- ng/ml for phenacetin and +/- 0.08 mug/ml for acetaminophen.

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PubMed1998

Acetaminophen alters estrogenic responses in vitro: stimulation of DNA synthesis in estrogen-responsive human breast cancer cells.

A limited number of studies have investigated the estrogenic potential of acetaminophen but none has reported its effects on breast cells. Many compounds that alter estrogen-mediated processes in various tissues contain p-phenolic moieties. Acetaminophen is a commonly used analgesic/antipyretic that also contains a p-phenol. This study tested the hypothesis that therapeutic concentrations of acetaminophen alter estrogen-responsive human breast cancer cell DNA synthesis. To this end, a modified E-screen assay was developed to determine the response to acetaminophen of two dichotomous types of human breast cancer cell lines: estrogen-responsive (MCF7, T47D, ZR-75-1) and estrogen-nonresponsive (MDA-MB-231, HS578T). Cells were placed in estradiol-free medium and then exposed to 3 nM estradiol or 0.03-1 mM acetaminophen. The proliferative response was assessed by determining [3H]thymidine incorporation into DNA and by determining the percentage of cells in the DNA synthesis (S) phase of the cell cycle. Concentrations of acetaminophen commonly attained in human plasma with therapeutic doses of this drug (approximately 0.1 mM) were found as effective as estradiol in stimulating DNA synthesis in estrogen-responsive breast cancer cells. Higher acetaminophen concentrations (1 mM) stimulated estrogen-responsive cells to a lesser extent. The combination of estradiol and acetaminophen did not stimulate DNA synthesis in estrogen-responsive cells more than either agent alone. Neither acetaminophen nor estradiol stimulated DNA synthesis in estrogen-nonresponsive human breast cancer cells. These novel findings demonstrate that therapeutic acetaminophen concentrations specifically stimulate estrogen-responsive breast cancer cell DNA synthesis, suggesting that this drug may exert estrogenic effects.

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PubMedDate not supplied

Influence of rifampicin on the toxicity and the analgesic effect of acetaminophen.

The influence of rifampicin on the toxicity, analgesic effect and pharmacokinetics of acetaminophen was studied in male albino mice. Repeated administration of rifampicin (50 mg/kg i.p. daily for 6 days) shortened hexobarbital sleeping time and increased liver weight, microsomal cytochrome P-450 and heme contents, NADPH-cytochrome c reductase and ethylmorphine-N-demethylase activities. Aniline hydroxylase activity was decreased and glucuronidation of p-nitrophenol was unaffected. Rifampicin pretreatment changed neither the LD50 of acetaminophen nor the hepatic glutathione level nor the glutathione depletion provoked by the toxic dose of acetaminophen (737 mg/kg p.o.). This suggests that rifampicin has no influence on the amount of acetaminophen toxic metabolites formed in the liver. Rifampicin decreased the acetaminophen analgesic effect in mice. Rifampicin decreased the Cmax, the half-time, the MRT and the AUC of acetaminophen and accelerated its clearance. The plasma concentration of acetaminophen glucuronide and acetaminophen sulfate was increased. It is assumed that the most probable mechanism by which rifampicin decreases acetaminophen analgesia is the accelerated acetaminophen elimination.

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PubMed1983

Acetaminophen-induced hepatic glycogen depletion and hyperglycemia in mice.

Two hours following administration of a hepatotoxic dose of acetaminophen (500 mg/kg, i.p.) to mice, liver sections stained with periodic acid Schiff reagent showed centrilobular hepatic glycogen depletion. A chemical assay revealed that following acetaminophen administration (500 mg/kg) hepatic glycogen was depleted by 65% at 1 hr and 80% at 2 hr, whereas glutathione was depleted by 65% at 0.5 hr and 80% at 1.5 hr. Maximal glycogen depletion (85% at 2.5 hr correlated with maximal hyperglycemia (267 mg/100 ml at 2.5 hr). At 4.0 hr following acetaminophen administration, blood glucose levels were not significantly different from saline-treated animals; however, glycogen levels were still maximally depleted. A comparison of the dose-response curves for hepatic glycogen depletion and glutathione depletion showed that acetaminophen (50-500 mg/kg at 2.5 hr) depleted both glycogen and glutathione by similar percentages at each dose. Since acetaminophen (100 mg/kg at 2.5 hr) depleted glutathione and glycogen by approximately 30%, evidence for hepatotoxicity was examined at this dose to determine the potential importance of hepatic necrosis in glycogen depletion. Twenty-four hours following administration of acetaminophen (100 mg/kg) to mice, histological evidence of hepatic necrosis was not detected and serum glutamate pyruvate transaminase (SGPT) levels were not significantly different from saline-treated mice. The potential role of glycogen depletion in altering the acetaminophen-induced hepatotoxicity was examined subsequently. When mice were fasted overnight, hepatic glutathione and glycogen were decreased by 40 and 75%, respectively, and fasted animals showed a dramatic increase in susceptibility to acetaminophen-induced hepatotoxicity as measured by increased SGPT levels. Availability of glucose in the drinking water (5%) overnight resulted in glycogen levels similar to those in fed animals, whereas hepatic glutathione levels were not significantly different from those of fasted animals. Fasted animals and animals given glucose water overnight were equally susceptible to acetaminophen-induced hepatotoxicity, as quantitated by increases in SGPT levels 24 hr after drug administration. The potential role of a reactive metabolite in glycogen depletion was investigated by treating mice with N-acetylcysteine to increase detoxification of the reactive metabolite. N-Acetylcysteine treatment of mice prevented acetaminophen-induced glycogen depletion.

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PubMed1984

Interaction of ethanol with acetaminophen metabolism in the baboon.

To evaluate the effects of ethanol on acetaminophen metabolism and toxicity, twelve female baboons were studied using three experimental designs. In the first one, animals fed ethanol chronically and their pair-fed controls received acetaminophen intravenously (40 mg/kg), and drug metabolism was studied for 6 hr in blood and urine. Elimination of acetaminophen from plasma was accelerated significantly in baboons fed alcohol chronically, and urinary excretion of mercapturic acid conjugate was increased. In the second, the experiments were repeated with the addition of ethanol infusion (120-160 mg/kg/hr). During ethanol infusion, elimination of acetaminophen from plasma was still accelerated significantly in baboons fed alcohol chronically. In the third experimental design, four pairs of baboons fed an alcohol or an isocaloric control liquid diet received, in addition, acetaminophen (85 mg/kg/day) in their respective liquid diets for 2 weeks. Liver histology was studied before and after acetaminophen feeding; SGPT, SGOT, SGDH, acetaminophen blood levels and acetaminophen urinary metabolites were also assessed. No morphological or functional liver alterations were found after chronic acetaminophen treatment, and urinary excretion of mercapturic acid conjugate was not increased in baboons fed alcohol chronically. Thus, our results in primates confirm that chronic ethanol consumption increases, whereas acute ethanol administration decreases, the excretion of mercapturic acid conjugate. When acute and chronic ethanol administration were combined, the effects tended to cancel each other out. A dose of acetaminophen which maintained blood levels similar to those recommended for humans did not produce deleterious effects in baboons drinking alcohol.

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PubMed1990

Acetaminophen-induced alterations in pancreatic beta cells and serum insulin concentrations in B6C3F1 mice.

Administration of acetaminophen (500 mg/kg) to male B6C3F1 mice resulted in alterations of pancreatic beta cell ultrastructure. These alterations were characterized by pronounced intercellular spaces, cytoplasmic vacuolization, damaged membranes of cytoplasm, secretory granules, and other organelles, and pyknotic nuclei with disrupted membranes. Concomitant with these changes, acetaminophen also caused increaes in serum insulin concentrations from 24 microU/ml at 0 time to 160 microU/ml at 8 hr and increases in serum alanine aminotransferase (ALT) concentrations from 42 to 13,279 U/liter, which indicated hepatic damage. Quantitation of 3-(cystein-S-yl)acetaminophen adducts in hepatic 10,000g supernatant protein using a particle concentration fluorescence immunochemical assay indicated a positive correlation between binding and the occurrence of the hepatotoxicity consistent with what has been previously reported; however, 3-(cystein-S-yl)acetaminophen protein adducts were not detected in pancreatic 10,000g supernatant. Immunohistochemical analysis of the liver and pancreas from acetaminophen-treated mice revealed acetaminophen-protein adducts in the centrilobular regions of the liver but not in the pancreatic islets. Doses of 100 and 200 mg/kg produced no evidence of hepatotoxicity and no increase in serum insulin; 300 mg/kg and higher doses produced both hepatotoxicity and increased serum insulin concentrations. A comparison of the time course for the increase in serum levels of ALT and insulin following a toxic dose of acetaminophen indicated that the increase in ALT preceded the increase in insulin. Thus the hepatotoxicity of acetaminophen correlates with the formation of 3-(cystein-S-yl)acetaminophen protein adducts in liver, which supports the concept that this toxicity is mediated by the reactive metabolite N-acetyl-p-benzoquinone imine; however, the toxicity of acetaminophen to beta cells in the pancreas is apparently not mediated by this mechanism.

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PubMed1988

Pharmacological studies on the in vivo cataractogenicity of acetaminophen in mice and rabbits.

Acetaminophen can be enzymatically bioactivated, which may play a role in cataractogenesis. This study evaluated the relation of dose, sex, plasma drug concentration, cytochromes P-450 (P-450 and P-448) induction, and hepatocellular toxicity to cataractogenic susceptibility in inbred mice and rabbits. C57BL/6 or DBA/2 mice, which respectively are genetically responsive and nonresponsive to P-448 induction, were treated with acetaminophen, 300 to 1000 mg/kg intraperitoneally (ip), following pretreatment with the P-448 inducer 3-methylcholanthrene (3-MC). Bilateral cataracts developed, independent of sex, in 83% of C57BL/6 mice within 4 hr of acetaminophen administration, compared with 7% of DBA/2 mice. A dose-response relation for cataractogenesis was evident in C57BL/6 mice using doses of 300 and 400 mg/kg, with the higher dose producing similar plasma acetaminophen concentrations but twofold higher glucuronide concentrations. Both strains had increased plasma concentrations of glutamic-pyruvic transaminase (GPT). New Zealand white or Chinchilla pigmented rabbits were treated with single or multiple doses of acetaminophen, 500 to 1500 mg/kg/day ip, following pretreatment with a cytochromes P-450 inducer: phenobarbital, 3-MC, or beta-naphthoflavone. Acetaminophen given chronically caused lenticular opacities within 1 week in 19 of 20 rabbits pretreated with P-450 inducers, regardless of pigmentation, but not in animals without prior P-450 induction. No opacities were observed after a single dose of acetaminophen, even with P-450 induction. There was no increase in plasma GPT in rabbits with any treatment. Over 85% of acetaminophen was recovered in urine as a glucuronide conjugate, and the rest as acetaminophen or conjugates with sulfate, cysteine, or N-acetylcysteine. Susceptibility to acetaminophen cataractogenesis can be genetically predetermined and may involve enzymatic bioactivation. possibly independent of hepatic biotransformation and toxicity.

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PubMed2005

Use of acetaminophen and the risk of self-reported allergic symptoms and skin sensitization in Butajira, Ethiopia.

BACKGROUND: Studies in developed countries suggest that acetaminophen use is associated with increased risk of asthma, but it is unclear whether this association is causal. OBJECTIVE: To determine the relation among acetaminophen use, asthma, and allergy, and to explore potential biases in acetaminophen use, in a developing country population. METHODS: We surveyed 7649 adults and children from Butajira, Ethiopia, collecting data on self-reported symptoms of allergic disease, skin sensitization to Dermatophagoides pteronyssinus and cockroach, acetaminophen use, and potential confounders. We then collected detailed data on indications for acetaminophen use and reasons for aspirin avoidance in a nested follow-up study. RESULTS: Allergic symptoms increased significantly with frequency of acetaminophen use, with odds ratios in those using >3 tablets in the past month relative to none 1.89 (95% CI, 1.51-2.36) for wheeze, 2.14 (1.72-2.67) for nocturnal shortness of breath, 2.52 (1.99-3.20) for rhinitis, and 1.90 (1.39-2.61) for eczema. Cockroach sensitization was also more common in the highest acetaminophen category (odds ratio, 1.40; 95% CI, 1.10-1.79), but D pteronyssinus sensitization was not. Less than 1% of participants with asthma or wheeze in our nested study reported avoidance of aspirin because of asthma symptoms. None volunteered using acetaminophen to treat allergic symptoms. CONCLUSION: There is a dose-related association between acetaminophen use and self-reported allergic symptoms in this population that is not a result of aspirin avoidance, reverse causation, or other bias. Acetaminophen may therefore be involved in the etiology of asthma and allergic disease.

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PubMed2003

Role of tumor necrosis factor receptor 1 (p55) in hepatocyte proliferation during acetaminophen-induced toxicity in mice.

Hepatocyte proliferation represents an important part of tissue repair. In these studies, TNF receptor 1 (TNFR1) knockout mice were used to analyze the role of TNF-alpha in hepatocyte proliferation during acetaminophen-induced hepatotoxicity. Treatment of wild-type (WT) mice with acetaminophen (300 mg/kg) resulted in centrilobular hepatic necrosis. This was associated with proliferation of hepatocytes surrounding the damaged areas, which was evident at 24 h. The cell cycle regulatory proteins, cyclin D1 and cyclin A, were also up regulated in hepatocytes. In contrast, in TNFR1-/- mice, which exhibit exaggerated acetaminophen hepatotoxicity, hepatocyte proliferation, and expression of cyclin D1 and cyclin A, as well as the cyclin dependent kinases, Cdk4 and Cdk2, were reduced. The cyclin-dependent kinase inhibitor p21 was also induced in the liver following acetaminophen administration. This was greater in TNFR1-/- mice compared to WT mice. To investigate mechanisms mediating the reduced hepatic proliferative response of TNFR1-/- mice, we analyzed phosphatidyl inositol-3-kinase (PI-3K) signaling. In both WT and TNFR1-/- mice, acetaminophen caused a rapid increase in total PI-3K within 3 h. Acetaminophen also increased phosphorylated PI-3K, but this was delayed 6-12 h in TNFR1-/- mice. Expression of Akt, a downstream target of PI-3K, was increased in both WT and TNFR1-/- mice in response to acetaminophen. However, the increase was greater in WT mice. Acetaminophen-induced expression of phosphorylated STAT3, a key regulator of cytokine-induced hepatocyte proliferation, was also delayed in TNFR1-/- mice relative to WT. These data suggest that TNF-alpha signaling through TNFR1 is important in regulating hepatocyte proliferation following acetaminophen-induced tissue injury. Delayed cytokine signaling may account for reduced hepatocyte proliferation and contribute to exaggerated acetaminophen-induced hepatotoxicity in TNFR1-/- mice.

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PubMed1988

Protective effects of selenium on acetaminophen-induced hepatotoxicity in the rat.

Experiments were undertaken to examine the ability of selenium to protect against acetaminophen-induced hepatotoxicity and to examine possible mechanisms for this protective effect. Pretreatment of male, Sprague-Dawley rats with sodium selenite (12.5 mumol Se/kg, ip) 24 hr prior to acetaminophen administration produced a significant protection against the hepatotoxic effects of acetaminophen as assessed by a decrease in the plasma appearance of alanine aminotransferase and aspartate aminotransferase activities following acetaminophen. This was accompanied by an increase in the hepatic glutathione levels in selenium-treated animals and an inhibition in the decrease in hepatic glutathione content observed in animals receiving hepatotoxic doses of acetaminophen. Selenium pretreatment decreased the in vivo covalent binding of acetaminophen metabolites to hepatic protein, but did not alter hepatic microsomal cytochrome P-450 content or NADPH cytochrome c reductase activity, suggesting that selenium does not significantly alter the metabolism of acetaminophen to reactive electrophilic metabolites by the cytochrome P-450-dependent mixed-function oxidase enzyme system. Selenium produced an increase in the activity of gamma-glutamylcysteine synthetase which may account for the increased glutathione availability in selenium-treated animals and increased the activities of glutathione S-transferase and glucose-6-phosphate dehydrogenase. Examination of the urinary metabolite profile in selenium-treated animals revealed that the urinary excretion of acetaminophen and its metabolites was significantly increased over a 72-hr period. The increase occurred in the AAP-glucuronide metabolite while parent AAP and AAP-sulfate were actually decreased in selenium-treated rats. No change in recovery was observed in the AAP-glutathione or AAP-mercapturate urinary metabolites. While the glutathione conjugating system is enhanced by selenium treatment, amelioration of acetaminophen toxicity is most likely the result of enhanced glucuronidation which effectively diverts the amount of acetaminophen to be converted by the cytochrome P-450 system to the toxic metabolite.

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PubMed1991

Simulated acetaminophen overdose: pharmacokinetics and effectiveness of activated charcoal.

STUDY OBJECTIVE: To determine the absorption rate of a supratherapeutic dose of acetaminophen elixir and compare the effect of activated charcoal (AC) given at different time intervals on preventing acetaminophen absorption. DESIGN: Randomized, nonblinded, crossover controlled study. SETTING: A certified regional poison control center. PARTICIPANTS: Ten healthy, adult male volunteers from 21 to 39 years old. INTERVENTIONS: Each subject received 5 g acetaminophen (elixir) on four occasions: a control phase plus 30 g of AC administered 15, 30, or 120 minutes after acetaminophen. Serum acetaminophen levels were obtained during the control phase only, and 24-hour urine collections were obtained during all four phases. MEASUREMENTS AND MAIN RESULTS: The highest serum acetaminophen levels were measured 1.4 +/- 0.52 hours after ingestion, and absorption was 97% complete by a mean of 2.05 hours. The administration of AC at 15, 30, and 120 minutes after acetaminophen reduced urinary recovery of acetaminophen and metabolites by 48%, 44%, and 33%, respectively. CONCLUSION: AC significantly reduces urinary recovery but not absorption of acetaminophen when administered two hours after acetaminophen elixir.

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PubMed2001

Acetaminophen elicits anti-estrogenic but not estrogenic responses in the immature mouse.

Acetaminophen is a widely used analgesic, which has exhibited evidence of estrogenic activity in estrogen-receptor positive human breast cancer cells. However, there is limited in vivo experimentation regarding the estrogenicity of acetaminophen. Therefore, the present study examined the in vivo estrogenic potential of acetaminophen using the immature female mouse model. Specifically, C57Bl/6 female mice were treated with acetaminophen (100, 200 and 250 mg/kg per day, i.p.) for 3 consecutive days. Positive controls received estradiol (10 microg/kg per day, i.p.) for 3 consecutive days. Markers of estrogenic activity examined were uterine weight, uterine peroxidase activity and progesterone receptor (PR) up-regulation. The results demonstrated that, at all three doses, acetaminophen did not significantly increase uterine weight, uterine peroxidase activity or PR levels. However, the co-administration of E(2) and acetaminophen (200 mg/kg per day, 3 days, i.p.) resulted in a decrease in the E(2)-induced upregulation of uterine and hepatic nuclear PR (uterine PR values of 39.7+/-6.6 and 23.7+/-3.4 fmol/mg for E(2)+vehicle and E(2)+acetaminophen, respectively, P<0.05). Additionally, the estradiol-induced increase in uterine peroxidase was decreased 75% by acetaminophen (200 mg/kg per day, 3 days, i.p.). Therefore, in the immature mouse model acetaminophen treatment did not elicit estrogenic activity. However, acetaminophen had a limited ability to antagonize the effects of E(2).

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PubMed2006

Influence of acetaminophen at therapeutic doses on surrogate markers of severity of acute viral hepatitis.

OBJECTIVES: Data on the influence of acetaminophen intake on acute viral hepatitis is scarce, but it could play a role in the worsening of this disease. The aim of this study was to determine whether the intake of acetaminophen at therapeutic doses affects the severity of acute viral hepatitis. METHODS: This was a prospective study concerning 37 consecutive patients hospitalized for acute viral hepatitis. Acetaminophen consumption and time since last intake were assessed by a questionnaire. Parameters of severity were studied in comparison to time related serum concentrations of acetaminophen. RESULTS: Patients hospitalized for acute viral hepatitis (18 male, 19 female patients) had a mean age of 29.2 +/- 11.5 years. The causal virus was HAV (n=23), HBV (n=7) and other viruses (n=8). The mean cumulated dose of acetaminophen was 7.7 +/- 5.65 g. The daily dose did not exceed the therapeutic dosage and the mean was 1.95 +/- 0.81 g (1-3 g). Patients who received 7.5 g of acetaminophen or more had a lower prothrombin index 52.4 +/- 30.3% vs 74.2 +/- 17.2% (P=0.039), and a lower factor V 54.7 +/- 33.2% vs 83.3 +/- 19.6% (P=0.033). Prothrombin index and bilirubinemia were negatively correlated with time related plasma acetaminophen concentrations. CONCLUSIONS: The use of acetaminophen at therapeutic doses was associated with greater alterations of surrogate markers of the severity of acute viral hepatitis especially hepatitis A. This was related to cumulated dosages and correlated to the time related acetaminophen plasma concentrations. Acetaminophen use should be interrupted when acute hepatitis is suspected.

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PubMed2000

Paracetamol (acetaminophen) hypersensitivity.

BACKGROUND: Acetaminophen (paracetamol) is an analgesic antipyretic drug with no antiinflammatory effects and is widely used worldwide. Earlier clinical studies reported IgE-mediated adverse reactions to acetaminophen, but in vivo and in vitro tests have been inconclusive. OBJECTIVE: We propose to demonstrate an IgE-mediated mechanism in four patients with adverse reactions to acetaminophen (paracetamol). Tolerance to aspirin and other nonsteroidal antiinflammatory drugs are present in all patients. METHODS: We studied four patients with anaphylactic reactions to acetaminophen who tolerated aspirin and other nonsteroidal antiinflammatory drugs. Skin tests, oral challenges and immunoassay for allergen-specific IgE antibodies with acetaminophen were performed in all patients. RESULTS: All patients tolerated the aspirin oral challenge without adverse effects. In contrast, the oral challenge with acetaminophen produced adverse effects in all patients. Skin tests with acetaminophen were positive in two patients (3-mm wheal and flare) and IgE antibodies acetaminophen were detected in serum from two patients. CONCLUSION: We describe four patients with adverse reactions to acetaminophen but with tolerance to aspirin and other nonsteroidal antiinflammatory drugs. Skin tests, oral challenges, and serum IgE results with acetaminophen suggest that an IgE-mediated mechanism is responsible for these reactions.

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