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PubMed2001

Effect of maximal daily doses of acetaminophen on the liver of alcoholic patients: a randomized, double-blind, placebo-controlled trial.

BACKGROUND: Retrospective reports suggest that therapeutic doses of acetaminophen may be associated with fulminant hepatic failure and death in alcoholic patients. Millions of patients use acetaminophen; the prevalence of alcoholism in the United States is 5% to 10%. OBJECTIVE: To determine if hepatic injury was associated with maximal therapeutic dosing of acetaminophen to chronic alcohol abuse patients immediately following cessation of alcohol intake (the presumed time of maximal vulnerability). METHODS: Patients entering an alcohol detoxification center were enrolled in a randomized, double-blind, placebo-controlled trial. Exclusion criteria were baseline values of aspartate or alanine aminotransferase greater than 120 U/L, international normalized ratio greater than 1.5, serum acetaminophen level greater than 20 mg/L, or a history of ingesting more than 4 g/d of acetaminophen. Acetaminophen, 1000 mg, or placebo was administered orally 4 times daily for 2 consecutive days and liver test results were monitored for 2 more days. Acetaminophen was not administered until the alcohol had been eliminated. RESULTS: There were 102 patients in the acetaminophen-treated group and 99 patients in the placebo-treated (control) group. Demographic data, alcohol history, and baseline blood test results were similar in both groups. The mean (SD) aspartate aminotransferase level on day 4 was 38.0 +/- 26.7 U/L in the acetaminophen-treated group and 37.5 +/- 27.6 U/L in the placebo-treated group. There were 4 patients in the acetaminophen-treated group and 5 in the placebo-treated group who developed an increase in their serum aspartate aminotransferase level to greater than 120 U/L; it did not exceed 200 U/L in any patient. The mean (SD) international normalized ratio on day 4 was 0.96 +/- 0.09 in the acetaminophen-treated group and 0.98 +/- 0.11 in the placebo-treated group. CONCLUSION: Repeated administration of the maximum recommended daily doses of acetaminophen to long-term alcoholic patients was not associated with evidence of liver injury.

Acetaminophen↗

PubMed1999

Acetaminophen-induced proliferation of breast cancer cells involves estrogen receptors.

Previous studies have shown that acetaminophen, a common analgesic/antipyretic, induces proliferation of cultured breast cancer cells containing both estrogen and progesterone receptors (ER+/PR+). The main objective of this study was to evaluate the involvement of ERs in this effect. First, the effects of therapeutic acetaminophen concentrations were compared in breast cancer cells with high ERs and in T47Dco cells with lower ERs, to determine if acetaminophen-induced proliferation depends on ER levels. Second, the effects of two antiestrogens (ICI 182,780 and 4'-hydroxytamoxifen) on acetaminophen-induced proliferation were determined in three human breast cancer cell lines: two ER+/PR+ (MCF7, T47D) and one ER-/PR- (MDA-MB-231). Third, ER binding assays were performed in MCF7 cells to determine if acetaminophen competed with estradiol for binding to ERs. Proliferation endpoints monitored included percent cells in the DNA synthesis phase of the cell cycle, 3H-thymidine incorporation into DNA, and cell number. Acetaminophen did not induce DNA synthesis in T47Dco cells, but did in cells with higher ER levels, suggesting high ER levels are necessary for acetaminophen to induce proliferation. Antiestrogens inhibited acetaminophen-induced proliferation in ER+/PR+ cells while no effects were observed in ER-/PR- cells, further supporting ER involvement. However, acetaminophen did not compete with estradiol for binding to ERs in ER+/PR+ cells. Collectively, these data suggest that acetaminophen induces breast cancer cell proliferation via ERs without binding to ERs like estradiol. The second purpose of this study was to determine if acetaminophen is estrogenic/antiestrogenic in vivo (uterotrophic assays). Acetaminophen has no antiestrogenic/estrogenic activity in mice or rats uteri.

Acetaminophen↗

PubMed1986

Biochemical changes associated with the potentiation of acetaminophen hepatotoxicity by brief anesthesia with diethyl ether.

Acetaminophen hepatotoxicity in male CD-1 mice was enhanced markedly by brief anesthesia with diethyl ether (ether), and particularly so if acetaminophen was given several hours after ether. The present study was conducted to examine the possible biochemical mechanisms behind this delayed toxicologic synergism. In vitro biochemical studies indicated that ether anesthesia produced a delayed reduction in the activities of glucuronyl transferase and glutathione (GSH) S-transferase, and in the hepatic content of GSH. The hepatic content but not activity of the cytochromes P-450 was initially reduced by ether but recovered by the time of maximal toxicologic enhancement. In vivo studies showed that ether produced a small decrease in the plasma concentrations of glucuronide and sulfate conjugates of acetaminophen, with a concomitant, minor increase in the half-life of acetaminophen, and a major increase in the bioactivation of acetaminophen, as determined by an early, 2-fold increase in the plasma GSH and cysteine conjugates of acetaminophen, and a 3-fold increase in the covalent binding of acetaminophen to hepatocellular protein. Decreases produced by ether in the in vivo production of acetaminophen glucuronide correlated with increasing plasma concentrations of unmetabolised acetaminophen, decreasing hepatic GSH content and increasing covalent binding of acetaminophen to hepatocellular protein when these measurements were performed in the same animals. The biochemical mechanisms underlying the potentiation of acetaminophen hepatoxicity as measured by plasma glutamic pyruvic transaminase concentrations appeared to be due to delayed, complex effects of ether upon multiple enzymatic pathways of acetaminophen elimination and detoxification.

Acetaminophen↗

PubMed1988

Metabolic evidence for the involvement of enzymatic bioactivation in the cataractogenicity of acetaminophen in genetically susceptible (C57BL/6) and resistant (DBA/2) murine strains.

Acetaminophen has been shown to be cataractogenic in mice and rabbits. C57BL/6 and DBA/2 mice respectively are genetically susceptible and resistant to the induction of cytochrome P-448 by 3-methylcholanthrene (3-MC). This isoenzyme is thought to bioactivate acetaminophen to a toxic reactive intermediate. These two murine strains also are correspondingly susceptible and resistant to acetaminophen cataractogenesis. To evaluate the potential role of enzymatic bioactivation as a determinant of acetaminophen cataractogenesis, C57BL/6 and DBA/2 mice were treated with acetaminophen, 300 or 400 mg/kg intraperitoneally (ip), with or without pretreatment 48 hr earlier using 3-MC, 200 mg/kg ip. Lenticular cataracts were evaluated using the unaided eye and a slit lamp, and hepatotoxicity was evaluated by determination of peak plasma concentration of alanine aminotransferase (ALT). Plasma concentrations of acetaminophen and metabolites, particularly the glutathione (GSH)-derived conjugates (cysteine and mercapturic acid) reflecting enzymatic bioactivation, were measured by high-performance liquid chromatography. Cataracts developed only in C57BL/6 mice pretreated with 3-MC, occurring in 1 of 5 and 5 of 5 animals treated respectively with 300 and 400 mg/kg of acetaminophen. Comparing these two groups of induced C57BL/6 mice, production of the cysteine conjugate of acetaminophen was 2.5-fold higher with the 400 mg/kg dose of acetaminophen (p less than 0.05). Compared to their respective dose-matched, noninduced controls, cysteine conjugate production in the 300 and 400 mg/kg dose groups of induced C57BL/6 mice respectively was 3-fold and 4-fold higher (p less than 0.05). No DBA/2 mice developed cataracts. No mercapturic acid conjugate was detectable in the plasma of DBA/2 mice, and production of the cysteine conjugate was not altered in this strain by increasing the dose of acetaminophen or by pretreatment with 3-MC. The mean peak plasma concentration of the cysteine conjugate, reflecting acetaminophen bioactivation, was 5-fold higher in animals developing cataracts compared with those without cataracts (p less than 0.001). Plasma concentrations of unmetabolized acetaminophen were similar in all groups and unrelated to the development of cataracts. All mice of both strains pretreated with 3-MC showed evidence of hepatotoxicity, indicating a dissociation between hepatotoxic and cataractogenic susceptibility.(ABSTRACT TRUNCATED AT 400 WORDS)

Acetaminophen↗

PubMed1992

Biotransformation and toxicity of acetaminophen in congenic RHA rats with or without a hereditary deficiency in bilirubin UDP-glucuronosyltransferase.

Acetaminophen is eliminated primarily by glucuronidation, thereby avoiding cytochrome P450-catalyzed bioactivation to a toxic reactive intermediate. Previous studies have shown that UDP-glucuronosyltransferase-deficient Gunn rats are more susceptible to acetaminophen toxicity than normal Wistar controls, from which the Gunn strain was derived. However, the Gunn and Wistar strains are not congenic, and differences in toxicologic susceptibility could be due in part to genetic differences other than UDP-glucuronosyltransferase activity. Accordingly, acetaminophen (750 mg/kg, ip) was administered to congenic RHA rats with normal (homozygous, RHA/++), moderately deficient (heterozygous, RHA/j+), and severely deficient (homozygous jaundiced, RHA/jj) activities of bilirubin UDP-glucuronosyltransferase. Acetaminophen metabolites were measured by high-performance liquid chromatography and production of the acetaminophen glucuronide conjugate was quantified by the area under plasma concentration-time curve (AUC) from 0 to 2 hr, standardized by the AUC value for acetaminophen in the same animal (glucuronidation ratio = AUC acetaminophen glucuronide/AUC acetaminophen). The 0- to 2-hr time period for AUC calculations was necessitated by the accumulation at later time points of glucuronide and sulfate conjugates in the plasma of animals experiencing severe nephrotoxicity. Acetaminophen bioactivation was quantified by the 24-hr urinary recovery of glutathione-derived conjugates. Hepatotoxicity and nephrotoxicity were assessed respectively by the peak concentrations of plasma alanine aminotransferase (ALT) and blood urea nitrogen (BUN). Glucuronidation of acetaminophen in RHA/jj rats (0.065 +/- 0.005) (mean +/- SE) was reduced 63% compared to the RHA/++ controls (0.17 +/- 0.01) (p < 0.05). RHA/jj rats demonstrated respective 230- and 7-fold increases in the peak plasma concentrations of ALT (17144 +/- 1014 vs 75 +/- 10) and BUN (128 +/- 23 vs 18.4 +/- 0.2) compared to congenic normal controls (RHA/++) (p < 0.05). Heterozygous animals (RHA/j+) demonstrated intermediary toxicity for both parameters (ALT = 2029 +/- 1581, BUN = 41 +/- 16, p < 0.05). Decreased glucuronide production correlated with elevations in ALT (r = -0.86, p < 0.001), while increased acetaminophen bioactivation correlated directly with both elevated ALT (r = 0.93, p < 0.001) and BUN (r = 0.83, p = 0.001). These results using congenic controls demonstrate that the enhanced susceptibility of UDP-glucuronosyltransferase-deficient rats to acetaminophen toxicity is due to decreased glucuronidation resulting in enhanced bioactivation, rather than to other unappreciated genetic differences.

Acetaminophen↗

PubMedDate not supplied

A comparative study of mouse liver proteins arylated by reactive metabolites of acetaminophen and its nonhepatotoxic regioisomer, 3'-hydroxyacetanilide.

Acetaminophen (4'-hydroxyacetanilide), a widely used analgesic/antipyretic drug, is hepatotoxic in large doses, whereas the m-hydroxy isomer of acetaminophen, 3'-hydroxyacetanilide, is not hepatotoxic. Both are oxidized by mouse liver cytochromes P-450 to reactive metabolites that bind covalently to hepatic proteins. Because previous studies have shown that peak levels of liver protein adducts formed after the administration of each of these compounds to mice are nearly equivalent, and because liver protein adduct formation correlates with hepatotoxicity caused by acetaminophen in mice, we investigated the abundance and patterns of protein adducts formed by acetaminophen and its regioisomer for significant differences. Hepatotoxic doses of acetaminophen to mice significantly altered the abundances of several liver proteins 2 h after dosing as revealed by densitometric analysis of two-dimensional electrophoretic patterns of these proteins. The same analysis after the administration to mice of 3'-hydroxyacetanilide indicated that this nonhepatotoxic regioisomer of acetaminophen caused several similar changes in protein patterns, but also revealed some significant differences. Binding of radiolabeled acetaminophen and 3'-hydroxyacetanilide to hepatic proteins corroborated and extended these results. Two hours after the administration of 14C-labeled analogs of these two compounds to mice, at a time when their extent of total covalent binding to hepatic proteins is approximately equivalent, there are many similarities but also some differences in selectivity of proteins that are adducted, as revealed by both one-dimensional and two-dimensional gel electrophoresis followed by phosphorimage analysis of radiolabel bound to protein bands. Moreover, protein adducts formed from 3'-hydroxyacetanilide were found to be less stable than those formed from acetaminophen under the conditions of electrophoretic analysis. Furthermore, a comparison of radiodetection and immunodetection of protein adducts formed from acetaminophen with an antibody specific for acetaminophen protein adducts indicates that the antibody detects most of the same proteins that are radiolabeled and that the relative quantitative contribution of various adducts to the overall covalent binding of acetaminophen to proteins is approximately the same by both methods. Thus, 3'-hydroxyacetanilide should prove to be a useful tool to aid in the discrimination of hepatic acetaminophen protein adducts that may be critical or noncritical to survival of hepatocytes.

Acetaminophen↗

PubMed2003

Acetaminophen exhibits weak antiestrogenic activity in human endometrial adenocarcinoma (Ishikawa) cells.

The purpose of this study was to test the hypothesis that acetaminophen would alter an estrogen-regulated process in human cells that express endogenous estrogen receptor alpha and beta (ERalpha and ERbeta). Specifically, the extent to which acetaminophen altered the expression of estrogen-inducible alkaline phosphatase in endometrial adenocarcinoma (Ishikawa) cells and directly interacted with ERbeta and ERalpha was determined. Ishikawa cells were exposed to estradiol and/or to a range of concentrations of acetaminophen for four days, and alkaline phosphatase activity was measured spectrophotometrically. Acetaminophen inhibited both basal and estradiol-induced alkaline phosphatase activity in Ishikawa cells in a concentration-dependent manner. The reduction of Ishikawa cell alkaline phosphatase was not due to direct inhibition of enzyme activity by acetaminophen. Toxic effects of acetaminophen on Ishikawa cells were determined by measuring loss of cellular lactate dehydrogenase to culture medium. High concentrations of acetaminophen (>/=0.5 mM) induced lactate dehydrogenase release from cells and reduced the amount of cellular protein in culture dishes, indicating some acetaminophen-induced reduction of alkaline phosphatase activity might be attributed to toxic effects. However, lower concentrations of acetaminophen significantly reduced alkaline phosphatase activity in the absence of detectable toxicity. Acetaminophen also augmented 4-hydroxy-tamoxifen reduction of alkaline phosphatase activity. Competition binding assays with human ERalpha and ERbeta demonstrated 10(6)-fold molar excess acetaminophen did not directly interact significantly with the ligand-binding domain of either receptor. These studies indicate acetaminophen exerts weak antiestrogenic activity in Ishikawa cells without directly binding ERalpha or ERbeta.

Acetaminophen↗

PubMed2005

Acetaminophen toxicity and resistance in the yeast Saccharomyces cerevisiae.

Acetaminophen (paracetamol), one of the most widely used analgesics, is toxic under conditions of overdose or in certain disease conditions, but the mechanism of acetaminophen toxicity is still not entirely understood. To obtain fresh insights into acetaminophen toxicity, this phenomenon was investigated in yeast. Acetaminophen was found to be toxic to yeast cells, with erg mutants displaying hypersensitivity. Yeast cells grown in the presence of acetaminophen were found to accumulate intracellular acetaminophen, but no metabolic products of acetaminophen could be detected in these extracts. The toxicity response did not lead to an oxidative stress response, although it did involve Yap1p. The cytochrome P450 enzymes of yeast, Erg5p and Erg11p, did not appear to participate in this process, unlike the mammalian systems. Furthermore, we could not establish a central role for glutathione depletion or the cellular glutathione redox status in acetaminophen toxicity, suggesting differences from mammalian systems in the pathways causing toxicity. Investigations of the resistance mechanisms revealed that deletion of the glutathione-conjugate pumps Ycf1p (a target of Yap1p) and Bpt1p, surprisingly, led to acetaminophen resistance, while overexpression of the multidrug resistance pumps Snq2p and Flr1p (also targets of Yap1p) led to acetaminophen resistance. The Yap1p-dependent resistance to acetaminophen required a functional Pdr1p or Pdr3p protein, but not a functional Yrr1p. In contrast, resistance mediated by Pdr1p/Pdr3p did not require a functional Yap1p, and revealed a distinct hierarchy in the resistance to acetaminophen.

ATP-Binding Cassette Transporters↗

PubMed2005

False positive acetaminophen levels associated with hyperbilirubinemia.

Serum acetaminophen determination is frequently necessary in patients with hepatic failure. We observed two patients (#1, #2) with elevated serum total bilirubin levels (26.5 mg/dL and 40.1 mg/dL) who had multiple false positive acetaminophen levels using the kinetic method of the GDS Diagnostics enzymatic acetaminophen assay (GDS Diagnostics, Elkhart, IN). We investigated the magnitude, threshold, and linearity of this effect using the GDS Diagnostics assay and an EMIT acetaminophen assay on two other hyperbilirubinemic patients (#3, #4) and a commercial solubilized bilirubin standard. Samples were diluted using fresh frozen plasma, and acetaminophen levels were analyzed twice using the kinetic method of the GDS Diagnostic acetaminophen assay and twice with the EMIT assay. The absence of acetaminophen in all samples was verified by gas chromatography/mass spectroscopy (GC/MS). The kinetic GDS assay resulted in a positive acetaminophen assay (cutoff for a positive result= 10 mg/L) with patient #3, patient #4, and in the bilirubin standard when the total bilirubin levels were 28.2 mg/dL, 22.5 mg/dL, and 18.3 mg/dL, respectively. One sample was interpolated to give a positive acetaminophen reading when diluted to a total bilirubin concentration of 15 mg/L. None of the samples tested with GC/MS or the EMIT assay resulted in any detectable acetaminophen. In conclusion, caution must be taken utilizing the GDS Diagnostic assay for the quantification of acetaminophen with concomitant hyperbilirubinemia. Alternatives such as EMIT or GC/MS should be employed to assess acetaminophen levels in such patients.

Acetaminophen↗

PubMed1986

Horseradish peroxidase-catalyzed oxidation of acetaminophen to intermediates that form polymers or conjugate with glutathione.

Horseradish peroxidase catalyzed the polymerization of acetaminophen. Addition of reduced glutathione (GSH) to reaction mixtures resulted in decreased polymerization and formation of minor amounts of GSH-acetaminophen conjugates. The conjugates were identified as 3-(glutathion-S-yl)acetaminophen and 3-(glutathion-S-yl)diacetaminophen. Horseradish peroxidase also catalyzed polymerization of synthetic 3-(glutathion-S-yl)acetaminophen to a dimer conjugate. In contrast to acetaminophen, 3-(glutathion-S-yl)acetaminophen oxidation was slowly catalyzed by horseradish peroxidase. However, in reaction mixtures containing equimolar concentrations of acetaminophen and synthetic 3-(glutathion-S-yl)acetaminophen, the formation of 3-(glutathion-S-yl)diacetaminophen and 3-(diglutathion-S-yl)diacetaminophen was rapid and accounted for approximately 95% of the products, whereas acetaminophen polymers accounted for only 5% of the products. These findings suggest that horseradish peroxidase catalyzed the one-electron oxidation of acetaminophen to N-acetyl-p-benzosemiquinone imine which preferentially polymerized rather than reacted with GSH. N-Acetyl-p-benzosemiquinone imine may also oxidize 3-(glutathion-S-yl)acetaminophen to form acetaminophen and 3-(glutathion-S-yl)-N-acetyl-p-benzosemiquinone imine. The data indicate that once this conjugate radical is formed it reacts with either N-acetyl-p-benzosemiquinone minine or 3-(glutathion-S-yl)-N-acetyl-p-benzosemiquinone imine via a radical termination mechanism.

Acetaminophen↗

PubMedDate not supplied

Effect of L-ascorbic acid on acetaminophen-induced hepatotoxicity and covalent binding in hamsters. Evidence that in vitro covalent binding differs from that in vivo.

The known potent inhibition of microsomally catalyzed covalent binding of acetaminophen by ascorbate has led to the suggestion that ascorbate rapidly reduces the reactive metabolite of acetaminophen and hence should protect against acetaminophen hepatotoxicity. Experimentally, ascorbate given immediately after acetaminophen did not protect against hepatotoxicity in the hamster and did not suppress in vivo covalent binding of acetaminophen. Ascorbate administration resulted in a rapid and marked increase in liver levels of reduced ascorbate. Hepatic ascorbate levels in both control and ascorbate-treated animals were unaffected by the administration of hepatic doses of acetaminophen. Also unchanged by ascorbate in vivo were the overall rate of acetaminophen elimination, acetaminophen-dependent depletion of hepatic glutathione, and the amount of acetaminophen-mercapturate excreted in the urine. Since these indices reflect the hepatic formation and fate of the reactive metabolite of acetaminophen, the data indicate that increased levels of ascorbate did not enhance reduction of the reactive metabolite of the drug back to acetaminophen in vivo, as was suggested from liver microsomal studies. Further studies examined the ascorbate sensitivity of the acetaminophen covalent binding reaction in ascorbate-deficient freshly isolated hepatocytes. In contrast with both the in vitro microsomal and the in vivo binding, covalent binding in the isolated hepatocyte was partially inhibitable by ascorbate. The ascorbate-insensitive binding, which represented approximately 50% of total binding, was inhibitable by cysteine. These data indicate that microsomally catalyzed covalent binding differs significantly from the covalent binding which occurs in the intact liver.

Acetaminophen↗

PubMed1981

Mechanism of the preventive effect of ethanol on acetaminophen-induced hepatoxicity.

Acute ethanol administration (6 g/kg p.o.) 6 hr before the injection of acetaminophen (0.5 g/kg i.p.) has been shown to prevent acetaminophen-induced hepatotoxicity in fasted young male Sprague-Dawley rats (b.wt. 90--130 g). By using this experimental model, the mechanism of this effect was studied. Covalent binding of reactive metabolite(s) of acetaminophen to hepatic proteins in vivo was less pronounced in ethanol-treated rats than in saline controls 2 and 6 hr after [3H]acetaminophen injection. Although hepatic reduced glutathione content was not affected by ethanol treatment, acetaminophen-induced depletion of reduced glutathione was partially prevented by ethanol. Urinary excretion of mercapturic acid was also decreased in ethanol-treated rats compared with saline controls. In isolated hepatocytes, ethanol partially prevented acetaminophen-induced depletion of reduced glutathione. These data suggested that ethanol decreases the production of reactive metabolite(s) from acetaminophen. Ethanol treatment did not decrease hepatic content of unmetabolized acetaminophen, the substrate of mixed-function oxidation, nor did it affect microsomal enzymes responsible for acetaminophen biotransformation to reactive metabolite(s). However, ethanol inhibited NADPH-dependent covalent binding of reactive metabolite(s) to microsomal protein as well as acetaminophen-induced spectral change. Thus, prevention of acetaminophen-induced hepatotoxicity by acute ethanol administration may be due to decreased production of reactive metabolite(s), most likely because of direct inhibition by ethanol of the biotransformation of acetaminophen to reactive metabolite(s).

Acetaminophen↗

PubMed1995

Sulfation and glucuronidation of acetaminophen by human hepatocytes cultured on Matrigel and type 1 collagen reproduces conjugation in vivo.

UNLABELLED: Our previous studies demonstrated marked sex differences in the metabolism of acetaminophen in rats both in vivo and in hepatocyte culture. This study examined the sex differences in human acetaminophen metabolism, and the ability to reproduce in vivo metabolism in human hepatocyte cultured on Matrigel vs. type 1 collagen. Human hepatocytes were isolated by collagenase perfusion of 10-15 g biopsies of patients without liver disease undergoing elective abdominal operations (8 females, age 41.3 +/- 19.3 years; 6 males, age 47.7 +/- 21.3 years). Postoperatively, patients were given 1 g of acetaminophen orally and a 24-hr urine collected to determine the metabolic fate. There were no sex differences in acetaminophen conjugation in vivo, nor in the hepatic acetaminophen sulfotransferase activities as observed in the rodents. Hepatocytes were cultured with acetaminophen (0, 150, 250, 500, and 1000 microM) on Matrigel and type I collagen. Acetaminophen glucuronidation predominated over acetaminophen sulfation just as in vivo without sex differences on days 1 and 2 in culture. By days 3 and 4, however, glucuronidation by female hepatocytes became enhanced compared with males. With increasing acetaminophen concentration (dose), there was a linear increase in sulfate and glucuronide conjugation without saturation of either pathway as observed in the rat. CONCLUSIONS: 1) there are no sex differences in acetaminophen metabolism or acetaminophen sulfotransferase activity as observed in the rat; 2) acetaminophen sulfation and glucuronidation by cultured human hepatocytes in vitro replicated in vivo metabolism on matrigel and type 1 collagen for the first 2 days in culture; and 3) glucuronidation became enhanced with time in the culture of female, but not male hepatocytes.

Acetaminophen↗

PubMed2006

Aminotransferase elevations in healthy adults receiving 4 grams of acetaminophen daily: a randomized controlled trial.

CONTEXT: During a clinical trial of a novel hydrocodone/acetaminophen combination, a high incidence of serum alanine aminotransferase (ALT) elevations was observed. OBJECTIVE: To characterize the incidence and magnitude of ALT elevations in healthy participants receiving 4 g of acetaminophen daily, either alone or in combination with selected opioids, as compared with participants treated with placebo. DESIGN, SETTING, AND PARTICIPANTS: A randomized, single-blind, placebo-controlled, 5-treatment, parallel-group, inpatient, diet-controlled (meals provided), longitudinal study of 145 healthy adults in 2 US inpatient clinical pharmacology units. INTERVENTION: Each participant received either placebo (n = 39), 1 of 3 acetaminophen/opioid combinations (n = 80), or acetaminophen alone (n = 26). Each active treatment included 4 g of acetaminophen daily, the maximum recommended daily dosage. The intended treatment duration was 14 days. Main Outcomes Serum liver chemistries and trough acetaminophen concentrations measured daily through 8 days, and at 1- or 2-day intervals thereafter. RESULTS: None of the 39 participants assigned to placebo had a maximum ALT of more than 3 times the upper limit of normal. In contrast, the incidence of maximum ALT of more than 3 times the upper limits of normal was 31% to 44% in the 4 treatment groups receiving acetaminophen, including those participants treated with acetaminophen alone. Compared with placebo, treatment with acetaminophen was associated with a markedly higher median maximum ALT (ratio of medians, 2.78; 95% confidence interval, 1.47-4.09; P<.001). Trough acetaminophen concentrations did not exceed therapeutic limits in any participant and, after active treatment was discontinued, often decreased to undetectable levels before ALT elevations resolved. CONCLUSIONS: Initiation of recurrent daily intake of 4 g of acetaminophen in healthy adults is associated with ALT elevations and concomitant treatment with opioids does not seem to increase this effect. History of acetaminophen ingestion should be considered in the differential diagnosis of serum aminotransferase elevations, even in the absence of measurable serum acetaminophen concentrations.

Acetaminophen↗

PubMed1993

Interaction of acetaminophen with myeloperoxidase intermediates: optimum stimulation of enzyme activity.

The myeloperoxidase-H2O2 system constitutes an effective physiological defense mechanism because of its ability to oxidize Cl- to HOCl, a powerful oxidizing agent, via the enzyme intermediate compound I. Two other oxidized intermediates, compounds II and III, are inactive in generation of HOCl. Acetaminophen, a safe drug at therapeutic doses but toxic at higher doses, was found to react with the oxidized intermediates of myeloperoxidase. Using steady-state kinetics on the chlorination of monochlorodimedon to measure the activity of myeloperoxidase, our study reveals that acetaminophen stimulates the chlorinating activity of the enzyme and optimum stimulation is achieved at about 30 microM. Increasing the concentration further causes a decline in the chlorination rate. The increase in enzyme activity at lower acetaminophen concentrations is accounted for by the increased turnover of compounds II and III to native enzyme, while the decline at higher acetaminophen concentrations is explained by the competition of acetaminophen with Cl- for compound I. Rapid scan and transient state kinetic results on the reaction of compound II and acetaminophen show that: (i) compound II does not pass through any other intermediate when acetaminophen reduces it back to native enzyme; and (ii) a simple binding interaction before enzyme reduction is involved. An apparent dissociation constant of 1.3 +/- 0.3 x 10(-4) M and a first-order rate constant for reduction of 37 +/- 4 s-1 were determined at 25 degrees C. Conventional spectral scans of the reaction between compound III and acetaminophen indicate that compound III goes back to native enzyme without any detectable intermediate. The rate of this reaction levels off at higher acetaminophen concentration. Rapid scans reveal that the reduction of compound I to compound II is faster in the presence of acetaminophen. Since the therapeutic concentrations of acetaminophen in man range approximately from 50 to 150 microM, the results of this study indicate that stimulation of myeloperoxidase activity is achieved within the safe dosage of the drug.

Acetaminophen↗

PubMed2002

Effect of inhibitors of nitric oxide synthase on acetaminophen-induced hepatotoxicity in mice.

We recently reported that following a toxic dose of acetaminophen to mice, tyrosine nitration occurs in the protein of cells that become necrotic. Nitration of tyrosine is by peroxynitrite, a species formed from nitric oxide (NO) and superoxide. In this manuscript we studied the effects of the NO synthase inhibitors N-monomethyl-l-arginine (l-NMMA), N-nitro-l-arginine methyl ester (NAME), l-N-(1-iminoethyl)lysine (l-NIL), and aminoguanidine on acetaminophen hepatotoxicity. Acetaminophen (300 mg/kg) increased serum nitrate/nitrite and alanine aminotransferase (ALT) levels, indicating increased NO synthesis and liver necrosis, respectively. None of the NO synthase inhibitors reduced serum ALT levels. In fact, l-NMMA, l-NIL, and aminoguanidine significantly augmented acetaminophen hepatotoxicity at 4 h. A detailed time course indicated that aminoguanidine (15 mg/kg at 0 h and 15 mg/kg at 2 h) significantly increased serum ALT levels over that for acetaminophen alone at 2 and 4 h; however, at 6 and 8 h serum ALT levels in the two groups were identical. At 2 h following acetaminophen plus aminoguanidine NO synthesis was significantly increased; however, at 4, 6, and 8 h NO synthesis was significantly decreased. Aminoguanidine also decreased acetaminophen-induced nitration of tyrosine. Acetaminophen alone did not induce lipid peroxidation, but acetaminophen plus aminoguanidine significantly increased hepatic lipid peroxidation (malondialdehyde levels) at 2, 4, and 6 h. These data are consistent with NO having a critical role in controlling superoxide-mediated lipid peroxidation in acetaminophen hepatotoxicity. Thus, acetaminophen hepatotoxicity may be mediated by either lipid peroxidation or by peroxynitrite.

Acetaminophen↗

PubMed2002

Acetaminophen-induced inhibition of Fas receptor-mediated liver cell apoptosis: mitochondrial dysfunction versus glutathione depletion.

We reported previously that acetaminophen overdose interrupts the signaling pathway of Fas receptor-mediated apoptosis. The aim of our study was to investigate the mechanism of this effect. Male C3Heb/FeJ mice received a single dose of acetaminophen (300 mg/kg ip) and/or anti-Fas antibody Jo-2 (0.6 mg/kg iv). Some animals were treated with allopurinol (100 mg/kg po) 18 and 1 h before acetaminophen injection. After 90 min of Jo treatment, there was processing of procaspase-3 and a significant increase in liver caspase-3 activity, which is consistent with apoptotic cell death. Treatment with acetaminophen 2.5 h before Jo inhibited the increase in hepatic caspase-3 activity by preventing the processing of the proenzyme. When administered alone, acetaminophen did not induce caspase-3 activation but caused significant liver injury. Acetaminophen treatment alone caused mitochondrial cytochrome c release, depletion of the hepatic ATP content by 55%, and a 10-fold increase in mitochondrial glutathione disulfide levels. Pretreatment with allopurinol prevented the mitochondrial oxidant stress and liver injury due to acetaminophen toxicity but had no effect on Jo-mediated apoptosis. Allopurinol did not affect the initial glutathione depletion after acetaminophen. However, allopurinol restored the sensitivity of hepatocytes to Fas receptor signaling in acetaminophen-treated animals. Histochemical evaluation of DNA fragmentation with the TUNEL assay showed that acetaminophen eliminated Fas receptor-mediated apoptosis in all hepatocytes not just in the damaged cells of the centrilobular area. Our data suggest that acetaminophen-induced mitochondrial dysfunction and not the initial glutathione depletion is responsible for the interruption of Fas receptor-mediated apoptotic signaling in hepatocytes.

Acetaminophen↗

PubMed1986

Delayed enhancement of acetaminophen hepatotoxicity by general anesthesia using diethyl ether or halothane.

Acetaminophen (Tylenol) is a widely used analgesic/antipyretic drug which is enzymatically bioactivated, or toxified, by the cytochromes P-450 to a hepatotoxic reactive intermediary metabolite. Brief general anesthesia with diethyl ether has been shown to inhibit both the toxifying cytochromes P-450 and enzymatic glucuronidation, the latter constituting up to 60% of acetaminophen elimination via a nontoxifying pathway. Thus ether potentially could produce a temporally differentiated inhibition of bioactivating and "detoxifying" pathways, resulting in an enhancement of acetaminophen hepatotoxicity if the balance favored bioactivation. To evaluate this possibility, separate groups of male NIH strain mice were treated with acetaminophen at different times after 5 min of anesthesia with ether. Ether produced a 40-fold enhancement in acetaminophen hepatotoxicity as determined by plasma glutamic-pyruvic transaminase (GPT) concentrations. This toxicologic enhancement was observed only if acetaminophen administration was delayed, with a maximal enhancement when acetaminophen was given 6 hr after ether, and no effect with a delay of 16 hr. Similar studies in male CD-1 mice were carried out using halothane (Fluothane) as the general anesthetic given either over 5 min or over 1 hr. While halothane given over 5 min had no effect, a 1 hr anesthetic duration produced a 10-fold increase in acetaminophen hepatotoxicity as determined by peak GPT concentration, with no observed hepatotoxicity in the halothane controls. Toxicologic enhancement occurred only with delayed administration of acetaminophen; however, the maximal enhancement observed with a 6-hr delay was still evident with a 12-hr delay. Conversely, inhibition of acetaminophen hepatotoxicity was observed if acetaminophen was given either 2 hr or 18 hr after halothane.(ABSTRACT TRUNCATED AT 250 WORDS)

Acetaminophen↗