Acetaminophen Exposure Research Articles

Prenatal acetaminophen exposure and risk of wheeze at age 5 years in an urban low-income cohort

BackgroundAcetaminophen has been associated with asthma and is in part metabolised via the glutathione pathway. Inner-city minority children have high asthma morbidity and a relatively high frequency of a minor...

Effects on feeding rate and biomarker responses of marine mussels experimentally exposed to propranolol and acetaminophen

Environmental risk assessments of human pharmaceuticals and other 'emerging contaminants' should integrate both population-relevant endpoints and biomarkers of potential modes of action in a range of species. Adult Mytilus galloprovincialis were exposed to the beta-adrenergic receptor blocker propranolol or to the anti-inflammatory drug acetaminophen (paracetamol), both commonly used therapeutic drugs present in aquatic ecosystems. Mussels were exposed under semi-static conditions for 10 days to either acetaminophen (CAS number 103-90-2; mean measured concentrations 23 and 403 microg/L) or propranolol hydrochloride (CAS number 318-98-9; mean measured propranolol concentrations 11 and 147 microg/L) at 15 +/- 1 degrees C sea water. Feeding rate was assessed as an indicator of general toxicity. For propranolol, the 10-day no-observed effect concentration ((feeding rate)NOEC) and lowest observed effect concentration ((feeding rate)LOEC) were 11 and 147 microg/L, respectively. For acetaminophen, feeding rate was increased at both 23 and 403 microg/L, suggesting a 10-day (feeding rate)NOEC of 403 microg/L. Primarily, phase I carboxylesterase (CbE), phase II glutathione S-transferase (GST) and the anti-oxidant catalase activities were evaluated in digestive gland. Gill GST and acetylcholinesterase (AChE) activities were also measured. Lipid peroxidation (LPO) levels were measured in both tissues to assess oxidative stress. Some enzymatic activities in liver were also reduced after propranolol exposure whilst acetaminophen enhanced them (CbE p < 0.05). Acetaminophen exposure significantly increased hepatic LPO levels and inhibited AChE activity in gill (10-day NOEC and LOEC of 23 and 403 microg/L, respectively), whereas propranolol (11 microg/L) enhanced gill GST.

Proteinuria is unrelated to the extent of acute acetaminophen overdose: A prospective clinical study

Acute renal failure is a recognized complication of acute acetaminophen overdose. Its detection depends on rising creatinine concentrations, which is an insensitive method. The present study examined whether proteinuria might correspond with the extent of acute acetaminophen exposure as a possible early marker of renal effects. A prospective case-control study included patients attending the emergency department within 24 hours of acetaminophen ingestion. A urine specimen was collected within 12 hours of hospital attendance for creatinine, albumin, and protein determination. Equivalent 4-hour acetaminophen concentrations were used to indicate drug exposure: mild if >100 g/L (>662 mmol/L), moderate if 100-200 g/L (662-1323 mmol/L), or severe if <200 g/L (<1323 mmol/L). Data are presented as median (interquartile range) and groups compared using Mann Whitney and chi-square tests. Seventy patients were studied (17 men, 53 women), age 37 years (23-45 years). The stated acetaminophen dose was 15 g (8-20 g), and interval between ingestion and presentation was 4.6 hours (4.1-7.9 hours). Urinary albumin concentrations were 8 mg/L (0-12 mg/L) in the mild group, 12 mg/L (5-25 mg/L) in the moderate group, and 11 mg/L (6-22 mg/L) in the severe group. Total protein concentrations were 90 mg/L (50-183 mg/L), 70 mg/L (40 to 130 mg/L), and 110 mg/L (75-205 mg/L), respectively. The proportions of patients who had urine albumin:creatinine ratio >3 mg/mmol were 20.8%, 23.5%, and 21.2%, respectively. None of the patients developed acute renal failure. No relationship was found between the extent of acute acetaminophen exposure and proteinuria. Further work is required to examine whether urinary protein excretion is altered in patients who subsequently develop acute renal failure following acetaminophen overdose.

Hepatic Mrp4 induction following acetaminophen exposure is dependent on Kupffer cell function

During acetaminophen (APAP) hepatotoxicity, increased expression of multidrug resistance-associated proteins 2, 3, and 4 (Mrp2-4) occurs. Mrp4 is the most significantly upregulated transporter in mouse liver following APAP treatment. Although the expression profiles of liver transporters following APAP hepatotoxicity are well characterized, the regulatory mechanisms contributing to these changes remain unknown. We hypothesized that Kupffer cell-derived mediators participate in the regulation of hepatic transporters during APAP toxicity. To investigate this, C57BL/6J mice were pretreated with clodronate liposomes (0.1 ml iv) to deplete Kupffer cells and then challenged with APAP (500 mg/kg ip). Liver injury was assessed by plasma alanine aminotransferase and hepatic transporter protein expression was determined by Western blot and immunohistochemistry. Depletion of Kupffer cells by liposomal clodronate increased susceptibility to APAP hepatotoxicity. Although increased expression of several efflux transporters was observed after APAP exposure, only Mrp4 was found to be differentially regulated following Kupffer cell depletion. At 48 and 72 h after APAP dosing, Mrp4 levels were increased by 10- and 33-fold, respectively, in mice receiving empty liposomes. Immunohistochemistry revealed Mrp4 staining confined to centrilobular hepatocytes. Remarkably, Kupffer cell depletion completely prevented Mrp4 induction by APAP. Elevated plasma levels of TNF-alpha and IL-1beta were also prevented by Kupffer cell depletion. These findings show that Kupffer cells protect the liver from APAP toxicity and that Kupffer cell mediators released in response to APAP are likely responsible for the induction of Mrp4.

Acute Acetaminophen Overdose Is Associated with Dose‐Dependent Hypokalaemia: A Prospective Study of 331 Patients

Hypokalaemia is a recognized complication of acute acetaminophen overdose. It is unclear whether this might be a pharmacological effect of acetaminophen, or due to association with confounding factors. The present study sought to better characterize the relationship between acetaminophen concentrations and risk of hypokalaemia. A prospective study of patients received N-acetylcysteine treatment within 15 hr of acute acetaminophen ingestion. Serum potassium concentrations were determined before and after N-acetylcysteine. Serum acetaminophen concentrations were used to indicate overall drug exposure by comparison to the Rumack-Matthew nomogram. Hypokalaemia was pre-defined by serum concentrations <3.5 mmol/l, and groups compared by Mann-Whitney tests. There were 331 patients. Median (95% confidence interval) fall in serum potassium concentration after N-acetylcysteine was 0.05 mmol/l (-0.11-0.30 mmol/l) if acetaminophen concentrations were below the 'high-risk' treatment line, 0.30 mmol/l (0.17-0.40 mmol/l) if between the 'high-risk' and 'normal' treatment lines (P = 0.0358), and 0.40 mmol/l (0.20-0.50 mmol/l) if above the 'normal' treatment line (P = 0.0136). A receiver operating characteristic showed that high acetaminophen concentrations were predictive of hypokalaemia (P = 0.0001 versus zero discriminatory line), and 4 hr acetaminophen concentration >156 mmol/l gave 81% sensitivity and 48% specificity. The risk of hypokalaemia after acute acetaminophen overdose depends on the extent of acetaminophen exposure, irrespective of N-acetylcysteine administration and independent of whether vomiting occurred. Acetaminophen appears to cause concentration-dependent hypokalaemia after overdose, and the pharmacological basis requires further consideration.

Simultaneous clustering of gene expression data with clinical chemistry and pathological evaluations reveals phenotypic prototypes

BackgroundCommonly employed clustering methods for analysis of gene expression data do not directly incorporate phenotypic data about the samples. Furthermore, clustering of samples with known phenotypes is typically performed in an informal fashion. The inability of clustering algorithms to incorporate biological data in the grouping process can limit proper interpretation of the data and its underlying biology.ResultsWe present a more formal approach, the modk-prototypes algorithm, for clustering biological samples based on simultaneously considering microarray gene expression data and classes of known phenotypic variables such as clinical chemistry evaluations and histopathologic observations. The strategy involves constructing an objective function with the sum of the squared Euclidean distances for numeric microarray and clinical chemistry data and simple matching for histopathology categorical values in order to measure dissimilarity of the samples. Separate weighting terms are used for microarray, clinical chemistry and histopathology measurements to control the influence of each data domain on the clustering of the samples. The dynamic validity index for numeric data was modified with a category utility measure for determining the number of clusters in the data sets. A cluster's prototype, formed from the mean of the values for numeric features and the mode of the categorical values of all the samples in the group, is representative of the phenotype of the cluster members. The approach is shown to work well with a simulated mixed data set and two real data examples containing numeric and categorical data types. One from a heart disease study and another from acetaminophen (an analgesic) exposure in rat liver that causes centrilobular necrosis.ConclusionThe modk-prototypes algorithm partitioned the simulated data into clusters with samples in their respective class group and the heart disease samples into two groups (sick and buff denoting samples having pain type representative of angina and non-angina respectively) with an accuracy of 79%. This is on par with, or better than, the assignment accuracy of the heart disease samples by several well-known and successful clustering algorithms. Following modk-prototypes clustering of the acetaminophen-exposed samples, informative genes from the cluster prototypes were identified that are descriptive of, and phenotypically anchored to, levels of necrosis of the centrilobular region of the rat liver. The biological processes cell growth and/or maintenance, amine metabolism, and stress response were shown to discern between no and moderate levels of acetaminophen-induced centrilobular necrosis. The use of well-known and traditional measurements directly in the clustering provides some guarantee that the resulting clusters will be meaningfully interpretable.

High-protein and high-carbohydrate breakfasts differentially change the transcriptome of human blood cells

Application of transcriptomics technology in human nutrition intervention studies would allow for genome-wide screening of the effects of specific diets or nutrients and result in biomarker profiles. The aim was to evaluate the potential of gene expression profiling in blood cells collected in a human intervention study that investigated the effect of a high-carbohydrate (HC) or a high-protein (HP) breakfast on satiety. Blood samples were taken from 8 healthy men before and 2 h after consumption of an HP or an HC breakfast. Both breakfasts contained acetaminophen for measuring the gastric emptying rate. Analysis of the transcriptome data focused on the effects of the HP or HC breakfast and of acetaminophen on blood leukocyte gene expression profiles. Breakfast consumption resulted in differentially expressed genes, 317 for the HC breakfast and 919 for the HP breakfast. Immune response and signal transduction, specifically T cell receptor signaling and nuclear transcription factor kappaB signaling, were the overrepresented functional groups in the set of 141 genes that were differentially expressed in response to both breakfasts. Consumption of the HC breakfast resulted in differential expression of glycogen metabolism genes, and consumption of the HP breakfast resulted in differential expression of genes involved in protein biosynthesis. Gene expression changes in blood leukocytes corresponded with and may be related to the difference in macronutrient content of the breakfast, meal consumption as such, and acetaminophen exposure. This study illustrates the potential of gene expression profiling in blood to study the effects of dietary exposure in human intervention studies.

Alterations in the Rat Serum Proteome during Liver Injury from Acetaminophen Exposure

Changes in the serum proteome were identified during early, fulminant, and recovery phases of liver injury from acetaminophen in the rat. Male F344 rats received a single, noninjury dose or a high, injury-producing dose of acetaminophen for evaluation at 6 to 120 h. Two-dimensional gel electrophoresis of immunodepleted serum separated approximately 800 stained proteins per sample from which differentially expressed proteins were identified by mass spectrometry. Serum alanine aminotransferase/aspartate aminotransferase levels and histopathology revealed the greatest liver damage at 24 and 48 h after high-dose acetaminophen corresponding to the time of greatest serum protein alterations. After 24 h, 68 serum proteins were significantly altered of which 23 proteins were increased by >5-fold and 20 proteins were newly present compared with controls. Only minimal changes in serum proteins were noted at the low dose without any histopathology. Of the 54 total protein isoforms identified by mass spectrometry, gene ontology processes for 38 unique serum proteins revealed involvement of acute phase response, coagulation, protein degradation, intermediary metabolism, and various carrier proteins. Elevated serum tumor necrosis factor-alpha from 24 to 48 h suggested a mild inflammatory response accompanied by increased antioxidant capability demonstrated by increased serum catalase activity. Antibody array and enzyme-linked immunosorbent assay analyses also showed elevation in the chemokine monocyte chemoattractant protein-1 and the metalloprotease inhibitor tissue inhibitor of metalloproteinases-1 during this same period of liver injury. This study demonstrates that serum proteome alterations probably reflect both liver damage and a concerted, complex response of the body for organ repair and recovery during acute hepatic injury.

CURCUMIN PRE‐EXPOSURE IN VIVO PREVENTS ACETAMINOPHEN‐INDUCED APOPTOTIC AND NECROTIC CELL DEATHS IN THE LIVER

Curcumin (CUR; diferuloylmethane), a rhizome extract of Curcuma longa is commonly used as a food coloring and flavoring agent. Although Oriental and the Ayurvedic medicines have traditionally used CUR in the treatment of diseases, conventional medicine has just begun to recognize its potential therapeutic value. Numerous experiments conducted by researchers around the globe have demonstrated CUR's ability to halt or prevent certain types of cancer, stop inflammation, and improve cardiovascular health. However, very few studies have examined its ability to protect against drug-induced organ injury. This study explored whether CUR pre-exposure has the potential to prevent acetaminophen (AP)-induced: (i) organ injuries (both hepatotoxicity and nephrotoxicity), in addition to (ii) apoptotic and necrotic cell deaths in the liver in vivo. Additional goals were to determine whether these events were linked to AP-induced oxidative stress, bcl-XL expression and the modes of cell death in the liver. In order to study CUR-AP interaction, male B6C3F1 mice were gavaged with CUR (17 mg/kg, p.o.) for 12 days followed by a single AP exposure(400 mg/kg, ip). Four groups of animals (Control, CUR, APAP, CUR+AP) were sacrificed 24h after AP exposure. Results indicated that AP-induced liver injury associated events, such as (ALT U/L:12 fold), lipid peroxidation (373%) and DNA fragmentation (325%) were considerably reduced to 3-fold, 89% and 104% respectively in CUR+AP group. AP-induced decrease in bcl-XL expression was also alleviated by CUR exposure and this change was mirrored in the pattern of apoptotic and necrotic cell deaths. It appears that CUR may impart global organoprotection against drug-induced organ toxicity by opposing events associated with both apoptosis and necrosis.

Children’s acetaminophen exposures reported to a regional poison control center

The patient characteristics, doses taken, and types of exposures in children with acetaminophen-related exposures reported to a regional poison control center (RPCC) were studied. A retrospective review was conducted of all acetaminophen exposures that occurred between October 31, 2000, and October 31, 2003, in children younger than 18 years who were managed by an RPCC. Children were grouped into three age categories: less than 6 years (group 1), 6-12 years (group 2), and 13-17 years (group 3). Data collected included patient demographics, drug details, type of exposure, time since exposure, exposure site, and caller site. There were 473 exposures to acetaminophen: 76% in group 1, 3% in group 2, and 21% in group 3. Sex was distributed equally among groups, except group 3 was 83% females. The majority of callers seeking information on acetaminophen ingestion in children younger than 12 years were family members (62%), whereas health professionals (61%) were the most common callers for children over 12 years. Unintentional ingestion was the most common type of exposure in group 1 (100%) and group 2 (93.7%). In group 3, intentional ingestions were more common (91%), with females representing far more of these exposures than males (87% versus 14%, respectively). Acetaminophen doses over 200 mg/kg were ingested by 47% of children in group 3. Most acetaminophen exposures reported to an RPCC occurred in children less than six years of age and were unintentional, whereas exposures in children over 12 years were more likely to be intentional overdoses.

Acetaminophen decreases intracellular glutathione levels and modulates cytokine production in human alveolar macrophages and type II pneumocytes in vitro

Recent epidemiological observations suggest that acetaminophen (paracetamol) may contribute to asthma morbidity. Impaired endogenous antioxidant defences may have a role in the pathogenesis of a number of inflammatory pulmonary diseases, including asthma. We studied the effect of acetaminophen on the intracellular level of reduced glutathione (GSH) with and without inhibitors of cytochrome P450 or prostaglandin H synthetase, and TNF-α, IL-6 and IL-8 protein production in human alveolar macrophages and type II pneumocytes in vitro. Following a 20 h incubation with acetaminophen, cytotoxicity was apparent from ≥5 and ≥10 mM in macrophages and type II pneumocytes, respectively. A time- and concentration-dependent decrease of intracellular GSH occurred after acetaminophen (0.05–1 mM) exposure (1–4 h) in pulmonary macrophages (up to 53%) and type II pneumocytes (up to 34%). Diethyldithiocarbamic acid, potassium ethyl xanthate, and indomethacin decreased significantly acetaminophen-induced GSH depletion in the two cell types tested, suggesting the involvement of cytochrome P450 (mainly CYP2E1) and/or prostaglandin H synthetase. In macrophages, acetaminophen decreased the secretion of TNF-α (at 4 and 24 h, concentration-related) and IL-6 (at 24 h, at 0.1 mM), and did not affect significantly IL-8 production. These in vitro observations demonstrate that clinically relevant concentrations of acetaminophen decreased: (i) intracellular GSH in human pulmonary macrophages and type II pneumocytes and (ii) the secretion of TNF-α and possibly IL-6 by human pulmonary macrophages. These findings provide experimental plausibility to the challenging observations that frequent use of APAP may be a risk factor for asthma morbidity.

Lipopolysaccharide-binding protein modulates acetaminophen-induced liver injury in mice

Acetaminophen toxicity is the most common cause of acute liver failure in the United States and Europe. Although much is known about the metabolism of acetaminophen, many questions remain regarding the pathogenesis of liver injury. In this study, we examined the role of lipopolysaccharide-binding protein (LBP), a protein important in mediating cellular response to lipopolysaccharides, by using LBP wild-type and knockout (KO) mice. We found that LBP KO mice were protected from acetaminophen-induced hepatotoxicity. At 350 mg/kg of acetaminophen, LBP KO mice had significantly less liver injury and necrosis than wild-type mice. Repletion studies in LBP KO mice using an LBP-adenoviral construct resulted in significantly more hepatic injury and necrosis after acetaminophen exposure compared with mice receiving the control adenoviral construct. In conclusion, LBP KO mice are protected from toxicity with a decrease in hepatic necrosis following acetaminophen challenge. This suggests a novel role for LBP in modulating acetaminophen-induced liver injury. Supplementary material for this article can be found on the HEPATOLOGY website (http://interscience.wiley.com/jpages/O270-9139/suppmat/index.html).

N-acetylcysteine does not protect HepG2 cells against acetaminophen-induced apoptosis.

Acetaminophen in large doses is well-known as hepatotoxic, and early therapy with N-acetylcysteine is frequently life-saving. However, in later stages of acetaminophen poisoning, treatment with N-acetylcysteine is not always effective. Although some of the pathways of acetaminophen toxicity and the effect of N-acetylcysteine have been elucidated, in depth information on this process is still lacking. Hepatoma-derived HepG2 cultured cells were exposed to acetaminophen (5 and 10 mM), with or without N-acetylcysteine (5 mM), for 24 and 48 hr. For the assessment of oxidative damage, apoptosis and necrosis, we followed redox status, glutathione content, nuclear fragmentation, phosphatidylserine externalization and ultrastructural changes. Variations in Ca2+ level and number of mitochondrial dense granules were also studied. Acetaminophen treatment of HepG2 cells caused oxidative damage and apoptosis. Significant decrease of cellular redox potential and glutathione content were time- and concentration-dependent. The protective effect of N-acetylcysteine was expressed by an increase of intracellular glutathione and of the level of metabolic reduction of the redox indicator Alamar Blue. The apoptogenic effect of acetaminophen was assessed by flow cytometry of annexin V binding, nuclear hypodiploidity, intracellular Ca2+, as well as by ultrastructural examination. Beyond 24 hr of acetaminophen exposure, necrosis was also noticed. We conclude that acetaminophen-induced oxidative damage in HepG2 cultured cells can be prevented by exposure to N-acetylcysteine. However, apoptosis, either early or late, here demonstrated, is not avoided by exposure to N-acetylcysteine. N-Acetylcysteine did not prevent acetaminophen-induced plasma membrane asymmetry, nuclear damage, alterations of Ca2+ homeostasis and ultrastructural changes.

Maternal use of acetaminophen and nonsteroidal anti-inflammatory drugs (NSAIDs), and muscular ventricular septal defects.

Muscular ventricular septal defects (mVSDs) are the most common congenital heart defects. Previous studies have suggested maternal use of acetaminophen or nonsteroidal anti-inflammatory drugs (NSAIDs), and/or fever as risk factors. We evaluated the association between mVSDs and maternal use of acetaminophen or NSAIDs adjusting for fever. Infants with nonsyndromic mVSDs (cases) and without birth defects (controls), with gestational age > or =37 weeks and their mothers were enrolled in the National Birth Defects Prevention Study. Two exposure periods were defined: the first trimester of pregnancy, and one month before pregnancy through delivery. Mothers reporting fever or medication use at least once during either period were considered exposed. Adjusted odds ratios and 95% confidence intervals were estimated independently for each exposure period. The analysis included 168 cases and 692 controls. Two case groups were evaluated: all mVSD infants (n = 168) (including those with associated minor cardiac defects or noncardiac defects), and infants with isolated mVSDs (n = 133). Mothers of cases were less likely to be African-American than Caucasian (OR, 0.36; 95% CI, 0.18, 0.73). Approximately equal numbers of case mothers and control mothers (10.4 versus 9.7%, respectively) reported at least one febrile episode during the first trimester. Neither acetaminophen nor NSAID exposure was significantly associated with mVSDs. This was true for both case groups and both exposure periods. Significant associations were not detected between the occurrence of mVSDs and maternal use of NSAIDs or acetaminophen adjusting for maternal fever, nor were they detected between maternal fever and mVSDs.

Activation of hepatic Nrf2 in vivo by acetaminophen in CD-1 mice.

The transcription factor NF-E2-related factor 2 (Nrf2) plays an essential role in the mammalian response to chemical and oxidative stress through induction of hepatic phase II detoxification enzymes and regulation of glutathione (GSH). Enhanced liver damage in Nrf2-deficient mice treated with acetaminophen suggests a critical role for Nrf2; however, direct evidence for Nrf2 activation following acetaminophen exposure was previously lacking. We show that acetaminophen can initiate nuclear translocation of Nrf2 in vivo, with maximum levels reached after 1 hour, in a dose dependent manner, at doses below those causing overt liver damage. Furthermore, Nrf2 was shown to be functionally active, as assessed by the induction of epoxide hydrolase, heme oxygenase-1, and glutamate cysteine ligase gene expression. Increased nuclear Nrf2 was found to be associated with depletion of hepatic GSH. Activation of Nrf2 is considered to involve dissociation from a cytoplasmic inhibitor, Kelch-like ECH-associated protein 1 (Keap1), through a redox-sensitive mechanism involving either GSH depletion or direct chemical interaction through Michael addition. To investigate acetaminophen-induced Nrf2 activation we compared the actions of 2 other GSH depleters, diethyl maleate (DEM) and buthionine sulphoximine (BSO), only 1 of which (DEM) can function as a Michael acceptor. For each compound, greater than 60% depletion of GSH was achieved; however, in the case of BSO, this depletion did not cause nuclear translocation of Nrf2. In conclusion, GSH depletion alone is insufficient for Nrf2 activation: a more direct interaction is required, possibly involving chemical modification of Nrf2 or Keap1, which is facilitated by the prior loss of GSH.

Association between acetaminophen or nonsteroidal antiinflammatory drugs and risk of developing ovarian, breast, or colon cancer.

To explore the association between exposure to acetaminophen (paracetamol) or nonsteroidal antiinflammatory drugs (NSAIDs) and risk of developing ovarian, breast, or colon cancer. Retrospective case-control study General practice offices. Four hundred eighty-three women with ovarian cancer and 1877 women matched for age, years of medical history in computer record, general practice attended, and calendar time; 3706 women with breast cancer and 14,155 matched control subjects; and 635 women with colon cancer and 2434 matched control subjects. United Kingdom-based General Practice Research Database was searched for women aged 50-89 years with a first-time diagnosis of ovarian, breast, or colon cancer and for matched controls to assess prescription analgesic exposure. Regular acetaminophen exposure (> or = 30 prescriptions) was associated with a slightly decreased risk of developing breast (odds ratio [OR] 0.8, 95% confidence interval [CI] 0.7-1.0) but not ovarian (OR 1.0, 95% CI 0.6-1.5) or colon (OR 1.0, 95% Cl 0.7-1.4) cancer. Regular NSAID exposure was associated with a reduced risk of colon (OR 0.5, 95% CI 0.3-0.9) but not ovarian or breast cancer. We found no evidence for a decreased ovarian cancer risk for women with regular acetaminophen or NSAID exposure.

Prospective evaluation of mild to moderate pediatric acetaminophen exposures

Study objective: To determine whether pediatric patients with acute, mild to moderate acetaminophen exposures, treated with home monitoring alone, develop systemic signs of hepatic injury. Methods: A prospective, observational study of calls to a regional poison center over a 25-month period was performed. Patients were eligible for the study if they were younger than 7 years and had an acute maximum possible acetaminophen exposure of up to 200 mg/kg. Exclusion criteria included previous decontamination measures, possibility of ingestion of an extended-release preparation, health or medication issues that could increase susceptibility to hepatotoxicity, current symptoms of hepatotoxicity, and indeterminable ingestions. Study protocol included reviewing the signs and symptoms of early and late acetaminophen toxicity, a 4- to 6-hour follow-up call, and a 72-hour follow-up call. Outcome measures were defined as a verbal report by the patient’s parent or guardian of the presence or absence of signs or symptoms of hepatotoxicity. Results: A total of 1,039 patients were enrolled in the study, including 519 girls and 520 boys, with exposures ranging from 20 to 200 mg/kg. Eighteen patients were lost to follow-up; data were incomplete for 2 patients. At 72-hour follow-up, the remaining 1,019 patients were all doing well, without signs or symptoms of hepatotoxicity. Conclusion: On the basis of these data, pediatric patients with acute acetaminophen exposures of up to 200 mg/kg, treated with home monitoring alone, do not develop signs or symptoms of hepatic injury. [Mohler CR, Nordt SP, Williams SR, Manoguerra AS, Clark RF. Prospective evaluation of mild to moderate pediatric acetaminophen exposures. Ann Emerg Med . March 2000;35:239-244.]

Impairment of TNF-α expression and secretion in primary rat liver cell cultures by acetaminophen treatment

Tumor necrosis factor-α (TNF-α) is assumed to act as a mediator in toxic liver injury, aggravating the primary damage to the parenchymal liver cell, but also stimulating liver regeneration. Reports on the effect of acetaminophen in vivo on TNF-α transcript concentrations and serum TNF-α concentrations, under different experimental, or clinical conditions have yielded controversial results. We used primary rat hepatocyte and Kupffer cell cultures to test the direct action of subtoxic and toxic concentrations of acetaminophen on TNF-α expression and release. We observed a dose-dependent decrease of TNF-α mRNA in the hepatocytes, and of TNF-α release into the medium of hepatocyte cultures. The data also indicate an impairment of TNF-α release in Kupffer cell cultures after treatment with nontoxic, as well as with toxic, acetaminophen concentrations. The results suggest that inhibition of TNF-α expression and release in the liver is a consequence of acetaminophen exposure. It is at present unknown how this effect modulates the course of acetaminophen intoxication.

Combination acetaminophen and doxapram potentiated hepatotoxicity in mouse primary cultured hepatocytes.

Doxapram-induced potentiation of acetaminophen-induced reductions in cell viability and apoptosis was examined in mouse primary cultured hepatocytes. Loss of viability following exposure of acetaminophen and/or doxapram in cultured hepatocytes was assessed by monitoring [3H]-thymidine incorporation and mitochondrial activity, and apoptosis of hepatocytes was determined by nuclear microscopic observation and from detection of a ladder-like DNA fragmentation pattern in agarose gel electrophoresis. The combination of acetaminophen (5 mM) and doxapram (10, 20, 50 or 100 microM) potentiated the reduction in cell viability and increased lipid peroxide levels of hepatocytes. Hepatocytes exposed for 24 h to acetaminophen (5 mM) plus doxapram (100 microM) showed atrophy of nuclei including chromatin condensation and a ladder-like DNA fragmentation pattern characteristic of apoptosis. Antioxidant (N-acetylcysteine), iron-chelator (deferoxamine), intracellular calcium ion chelator (quin 2-AM), endonuclease inhibitor (aurintricarboxylic acid) and poly (ADP-ribose) polymerase inhibitor (3-aminobenzamide) all improved the viability of cells and eliminated the ladder-like DNA fragmentation in cells exposed to acetaminophen plus doxapram. In conclusion, the combination acetaminophen and doxapram potentiated the reduction in cell viability and apoptosis in mouse primary cultured hepatocytes. We suggest that careful observation for hepatotoxicity is recommended when acetaminophen and doxapram are prescribed simultaneously.

Fetal growth and adverse birth outcomes in women receiving prescriptions for acetaminophen during pregnancy. EuroMap Study Group.

We studied the association between acetaminophen exposure during pregnancy and the prevalence of congenital abnormalities and fetal growth. Our study included 123 women who had received a prescription of acetaminophen during pregnancy and/or 30 days before conception and 13,329 controls who did not receive any prescription at all. We found more malformations among those who received a prescription with an odds ratio of 2.3 (95% CI 1.0-5.4), but the type of malformations did not indicate a causal link. When restricting the study to first time pregnancies, we identified 58 women who received a prescription of acetaminophen during pregnancy and 30 days before conception and 7472 controls. We found no excess risk of malformation [OR = 0.7 (95% CI 0.1-5.5)], and no evidence that acetaminophen should influence fetal growth.