Acetaminophen Hepatotoxicity -- Neurotransmitter.net

Rumack BH.
Acetaminophen hepatotoxicity: the first 35 years.
J Toxicol Clin Toxicol 2002;40(1):3-20
"A critical understanding of the literature makes it clear that therapeutic doses of acetaminophen either alone or in the presence of inducers do not produce toxicity. While the community of clinical toxicologists is small, it needs to be more aggressive in making sure that physicians from other specialties and non-clinical toxicology colleagues understand the significance and implications of this science." [Abstract]

Brok J, Buckley N, Gluud C.
Interventions for paracetamol (acetaminophen) overdoses (Cochrane Review).
Cochrane Database Syst Rev 2002;(3):CD003328
"N-acetylcysteine should be given to patients with paracetamol overdose. No N-acetylcysteine regime has been shown to be more effective than any other." [Abstract]

Krenzelok EP.
New developments in the therapy of intoxications.
Toxicol Lett 2002 Feb 28;127(1-3):299-305
"Multiple dose activated charcoal and urinary alkalinization, commonly used to enhance the elimination of some poisons, have limited usefulness. While these 'old' and more general methods of 'detoxification' have thus failed in most cases to improve or change patient outcome, the use of more specific antidotes, tailored to the exact cause of intoxication is to be considered. Very few antidotes, however, are used on a consistent basis in the management of poisoned victims. The indiscriminate use of antidotes may even be harmful to the patient and incur an inordinate expense. In addition to the commonly known antidotes N-acetylcysteine (acetaminophen, paracetamol), naloxone (opioids) and flumazenil (benzodiazepines), new antidotes include fomepizole to treat ethylene glycol and methanol poisoning and Crotalidae Polyvalent Immune Fab (Ovine) for pit viper envenomation." [Abstract]

Gyamlani GG, Parikh CR.
Acetaminophen toxicity: suicidal vs. accidental.
Crit Care 2002 Apr;6(2):155-9
"Acetaminophen toxicity, which can lead to hepatotoxicity, is a burden on our health care system and contributes significantly to intensive care unit admissions and cost of hospitalization. The aim of our study was to determine the epidemiology of various types of acetaminophen poisoning and analyze their outcome compared with their admission characteristics." [Full Text]

Lifshitz M, Gavrilov V.
Deliberate self-poisoning in adolescents.
Isr Med Assoc J 2002 Apr;4(4):252-4
"We evaluated 324 cases of adolescent self-poisoners aged 12-18 years (mean +/- SD 14.8 +/- 1.5 years). The female/male ratio was 8:1. Most of the patients were attending school and lived in urban areas. Oral ingestion was the only route of intake; 84.5% of the patients ingested drugs and 10.5% non-medicinal compounds. The drug most commonly taken was acetaminophen." [Abstract]

Shah R, Uren Z, Baker A, Majeed A.
Trends in suicide from drug overdose in the elderly in England and Wales, 1993-1999.
Int J Geriatr Psychiatry 2002 May;17(5):416-21
"Drugs most commonly used in overdose were (in order) paracetamol (and related compounds), benzodiazepines, antidepressants, and opiates." [Abstract]

Lucanie R, Chiang WK, Reilly R.
Utility of acetaminophen screening in unsuspected suicidal ingestions.
Vet Hum Toxicol 2002 Jun;44(3):171-3
"Although the overall risk of unsuspected acetaminophen toxicity in suicidal ingestions is small, the definite risk in this treatable entity warrants universal APAP screening in all suicidal ingestions." [Abstract]

Schiodt FV, Ott P, Christensen E, Bondesen S.
The value of plasma acetaminophen half-life in antidote-treated acetaminophen overdosage.
Clin Pharmacol Ther 2002 Apr;71(4):221-5 [Abstract]

Buckley NA, Srinivasan J.
Should a lower treatment line be used when treating paracetamol poisoning in patients with chronic alcoholism?: a case for.
Drug Saf 2002;25(9):619-24 [Abstract]

Dargan PI, Jones AL.
Should a lower treatment line be used when treating paracetamol poisoning in patients with chronic alcoholism?: a case against.
Drug Saf 2002;25(9):625-32 [Abstract]

Zhao P, Kalhorn TF, Slattery JT.
Selective mitochondrial glutathione depletion by ethanol enhances acetaminophen toxicity in rat liver.
Hepatology 2002 Aug;36(2):326-35
"In conclusion, 10-day ethanol feeding enhances APAP toxicity through CYP2E1 induction, whereas 6-week ethanol feeding potentiates APAP hepatotoxicity by inducing CYP2E1 and selectively depleting mitochondrial GSH." [Abstract]

Neuman MG.
Synergetic signaling for apoptosis in vitro by ethanol and acetaminophen.
Alcohol 2002 Jun;27(2):89-98 [Abstract]

Purssell E.
Treating fever in children: paracetamol or ibuprofen?
Br J Community Nurs 2002 Jun;7(6):316-20
"Eight randomized controlled trials that reported temperature differences at time-points between 1 and 6 hours after administration were identified. Statistical meta-analysis showed no clear benefit for one drug over another 1 hour after administration. However, by 6 hours after administration ibuprofen was clearly superior resulting in a mean temperature 0.58 degrees C lower than paracetamol. Both drugs appeared well tolerated and no evidence of difference in short-term adverse effects was observed. Both drugs are effective antipyretics but the longer action of ibuprofen may make it preferable in some circumstances." [Abstract]

Warms CA, Turner JA, Marshall HM, Cardenas DD.
Treatments for chronic pain associated with spinal cord injuries: many are tried, few are helpful.
Clin J Pain 2002 May-Jun;18(3):154-63
"Respondents reported multiple pain treatments (range of 0-14 and median of 4 in sample 1; range of 0-16 and median of 4 in sample 2). The most commonly reported treatments were oral medications and physical therapy. Medication types most commonly reported were nonsteroidal anti-inflammatory drugs (NSAIDs), acetaminophen, and opioids. The treatments rated as most helpful were opioid medications, physical therapy, and diazepam therapy, and those rated as least helpful were spinal cord stimulation, counseling or psychotherapy, administration of acetaminophen, and administration of amitriptyline. Alternative treatments reported as most helpful were massage therapy and use of marijuana. Acupuncture was tried by many but was rated as only moderately helpful." [Abstract]

Anikwue R, Huffman JW, Martin ZL, Welch SP.
Decrease in efficacy and potency of nonsteroidal anti-inflammatory drugs by chronic delta(9)-tetrahydrocannabinol administration.
J Pharmacol Exp Ther 2002 Oct;303(1):340-6
"When NSAIDs (p.o.) were administered, the ED(50) values were as follows: 23 mg/kg aspirin, 3 mg/kg indomethacin, 5 mg/kg celecoxib, 3 mg/kg ketorolac, 57 mg/kg acetaminophen (32.3-99.8), and 0.8 mg/kg diclofenac (0.1-4.9). In animals given chronic Delta(9)-THC, only diclofenac and acetaminophen were active. Conversely, chronic methanandamide (i.p.) did not alter the antinociceptive effects of the NSAIDs. Neither the CB1 or CB2 antagonist blocked the effects of the NSAIDs. The effects of chronic arachadonic acid, ethanolamine, and anandamide could not be evaluated. In summary, our data indicate that chronic Delta(9)-THC alters the cyclooxygenase system. Alternatively, the data suggest that this alteration is not due to chronic endogenous cannabinoid release. Based upon these data, we hypothesize that human subjects who are chronic users of Delta(9)-THC may not respond to analgesic treatment with the above NSAIDs." [Abstract]

N. V. Chandrasekharan, Hu Dai, K. Lamar Turepu Roos, Nathan K. Evanson, Joshua Tomsik, Terry S. Elton, and Daniel L. Simmons
COX-3, a cyclooxygenase-1 variant inhibited by acetaminophen and other analgesic/antipyretic drugs: Cloning, structure, and expression PNAS published September 19, 2002, 10.1073/pnas.162468699
"Comparison of canine COX-3 activity with murine COX-1 and -2 demonstrates that this enzyme is selectively inhibited by analgesic/antipyretic drugs such as acetaminophen, phenacetin, antipyrine, and dipyrone, and is potently inhibited by some nonsteroidal antiinflammatory drugs. Thus, inhibition of COX-3 could represent a primary central mechanism by which these drugs decrease pain and possibly fever." [Abstract]

Pierce RH, Franklin CC, Campbell JS, Tonge RP, Chen W, Fausto N, Nelson SD, Bruschi SA.
Cell culture model for acetaminophen-induced hepatocyte death in vivo.
Biochem Pharmacol 2002 Aug 1;64(3):413-24
"Overdose of the popular, and relatively safe, analgesic acetaminophen (N-acetyl-p-aminophenol, APAP, paracetamol) can produce a fatal centrilobular liver injury. APAP-induced cell death was investigated in a differentiated, transforming growth factor alpha (TGFalpha)-overexpressing, hepatocyte cell line and found to occur at concentrations, and over time frames, relevant to clinical overdose situations. Coordinated multiorganellar collapse was evident during APAP-induced cytotoxicity with widespread, yet selective, protein degradation events in vitro. Cellular proteasomal activity was inhibited with APAP treatment but not with the comparatively nonhepatotoxic APAP regioisomer, N-acetyl-m-aminophenol (AMAP). Low concentrations of the proteasome-directed inhibitor MG132 (N-carbobenzoxyl-Leu-Leu-Leucinal) increased chromatin condensation and cellular stress responses preferentially in AMAP-treated cultures, suggesting a contribution of the proteasome in APAP- but not AMAP-mediated cell death. APAP-specific alterations to mitochondria were observed morphologically with evidence of mitochondrial proliferation in vitro. Biochemical alterations to cellular proteolytic events were also found in vivo, including APAP- or AMAP-mediated inhibition of caspase-3 processing. These results indicate that, although retaining some attributes of apoptosis, both APAP- and AMAP-mediated cell death have additional distinctive features consistent with longer term necrosis."
[Abstract]
Haouzi D, Cohen I, Vieira HL, Poncet D, Boya P, Castedo M, Vadrot N, Belzacq AS, Fau D, Brenner C, Feldmann G, Kroemer G.
Mitochondrial permeability transition as a novel principle of hepatorenal toxicity in vivo.
Apoptosis 2002 Oct;7(5):395-405
"Acetaminophen (paracetamol)-induced acute poisoning was also attenuated by CsA and GSH, both in vitro and in vivo. Altogether these data indicate that PTPC-mediated MMP may determine the hepatorenal toxicity of xenobiotics in vivo."
[Abstract]
Ishida Y, Kondo T, Ohshima T, Fujiwara H, Iwakura Y, Mukaida N.
A pivotal involvement of IFN-gamma in the pathogenesis of acetaminophen-induced acute liver injury.
FASEB J 2002 Aug;16(10):1227-36
"All IFN-gamma-deficient mice survived with reduced serum transaminase elevation and attenuated hepatic necrosis, leukocyte infiltration, and hepatocyte apoptosis. The gene expression of all molecules was significantly attenuated in IFN-gamma-deficient mice. Administration of an anti-IFN-gamma neutralizing antibody even 2 or 8 h after APAP challenge to wild-type mice alleviated APAP-induced liver injury, and all mice survived. Thus, IFN-gamma is responsible for APAP-induced liver injury by mediating leukocyte infiltration, hepatocyte apoptosis, and NO production as well as cytokine and chemokine production. Moreover, immunoneutralization of IFN-gamma may be therapeutically effective for developing APAP-induced liver injury." [Abstract]

Schmidt LE, Dalhoff K.
Serum phosphate is an early predictor of outcome in severe acetaminophen-induced hepatotoxicity.
Hepatology 2002 Sep;36(3):659-65 [Abstract]
Nagai H, Matsumaru K, Feng G, Kaplowitz N.
Reduced glutathione depletion causes necrosis and sensitization to tumor necrosis factor-alpha-induced apoptosis in cultured mouse hepatocytes.
Hepatology 2002 Jul;36(1):55-64
"A combination of antioxidants, vitamin E, and butylated hydroxytoluene (BHT) markedly inhibited necrosis induced by APAP or DEM alone, but the sensitization to TNF-alpha-induced apoptosis was unaffected." [Abstract]
Chiu H, Brittingham JA, Laskin DL.
Differential induction of heme oxygenase-1 in macrophages and hepatocytes during acetaminophen-induced hepatotoxicity in the rat: effects of hemin and biliverdin.
Toxicol Appl Pharmacol 2002 Jun 1;181(2):106-15
"Pretreatment of rats with hemin was found to prevent acetaminophen-induced hepatotoxicity, as measured histologically and biochemically by decreased serum transaminase levels. This was correlated with more rapid increases in expression of hepatic ferritin and MnSOD. Heme metabolism via HO-1 generates biliverdin, which is rapidly converted to bilirubin by biliverdin reductase. Pretreatment of rats with biliverdin (40 micromol/kg, ip) was also found to block acetaminophen-induced injury. These data suggest that HO-1 is an important component of antioxidant defense during acetaminophen-induced hepatotoxicity." [Abstract]
Knight TR, Jaeschke H.
Acetaminophen-induced inhibition of Fas receptor-mediated liver cell apoptosis: mitochondrial dysfunction versus glutathione depletion.
Toxicol Appl Pharmacol 2002 Jun 1;181(2):133-41 [Abstract]
Shirota FN, DeMaster EG, Shoeman DW, Nagasawa HT.
Acetaminophen-induced suppression of hepatic AdoMet synthetase activity is attenuated by prodrugs of L-cysteine.
Toxicol Lett 2002 Jun 7;132(1):1-8 [Abstract]
Bourdi M, Reilly TP, Elkahloun AG, George JW, Pohl LR.
Macrophage migration inhibitory factor in drug-induced liver injury: a role in susceptibility and stress responsiveness.
Biochem Biophys Res Commun 2002 Jun 7;294(2):225-30
"The decreased hepatic injury in MIF-/- mice correlated with a reduction in mRNA levels of interferon-gamma and a significant increase in heat shock protein expression, but was unrelated to the APAP-protein adduct formation in the liver. These findings support MIF as a critical pro-toxicant signal in drug-induced liver injury with potentially important and novel effects on heat shock protein responsiveness." [Abstract]
Yamazaki R, Kusunoki N, Matsuzaki T, Hashimoto S, Kawai S.
Nonsteroidal anti-inflammatory drugs induce apoptosis in association with activation of peroxisome proliferator-activated receptor gamma in rheumatoid synovial cells.
J Pharmacol Exp Ther 2002 Jul;302(1):18-25 [Abstract]

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Recent Acetaminophen and Hepatotoxicity Research
1) Campion SN, Johnson R, Aleksunes LM, Goedken MJ, van Rooijen N, Scheffer GL, Cherrington NJ, Manautou JE
Hepatic Mrp4 Induction Following Acetaminophen Exposure is Dependent on Kupffer Cell Function.
Am J Physiol Gastrointest Liver Physiol. 2008 Jun 12;
During acetaminophen (APAP) hepatotoxicity, increased expression of multidrug resistance-associated proteins 2, 3 and 4 (Mrp2-4) occurs. Mrp4 is the most significantly up-regulated transporter in mouse liver following APAP treatment. While 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 i.v.) to deplete Kupffer cells and then challenged with APAP (500mg/kg i.p.). 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. While 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 hrs 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. Key words: multidrug resistance protein, hepatotoxicity, macrophage. [PubMed Citation] [Order full text from Infotrieve]

2) Fukumoto M
[Analytic role in clinical toxicology--impact on the diagnosis and treatment of a poisoned patient]
Rinsho Byori. 2008 Apr;56(4):330-4.
The measurement of plasma or urine levels of drugs or toxins at an appropriate time after ingestion and assessment of the clinical status can have a significant impact in the clinical management of a poisoned patient. Qualitative screening of blood and urine is helpful in identifying ingested toxins, whereas quantitative analyses are useful in determining appropriate therapy with selected toxins (e.g., salicylate, paraquat, and acetaminophen). The common analgesic acetaminophen, which is available without prescription, is a potential hepatotoxin on overdose. The most widely accepted approach to determine the risk of hepatotoxicity following acute, single ingestion is to plot the plasma acetaminophen concentration on the Rumack-Matthew nomogram. This nomogram is based on a series of patients with and without hepatotoxicity and their corresponding blood levels. Antidotal treatment should be administered to any patient with a plasma level in the potentially toxic range. As an aid in the diagnosis and treatment of toxic incidents, as well as in monitoring the effectiveness of treatment regimens, an analytical approach is useful to clearly identify the nature of the toxic exposure and measure the amount of the toxic substance which has been absorbed. A cardinal rule in the treatment of poisoning cases is to remove any unabsorbed material, limit the absorption of additional poison, and hasten its elimination. The laboratory serves an additional purpose in the treatment phase by monitoring the amount of toxic agent remaining in circulation or measuring that excreted. [PubMed Citation] [Order full text from Infotrieve]

3) Donthamsetty S, Bhave VS, Mitra MS, Latendresse JR, Mehendale HM
Nonalcoholic steatohepatitic (NASH) mice are protected from higher hepatotoxicity of acetaminophen upon induction of PPARalpha with clofibrate.
Toxicol Appl Pharmacol. 2008 Mar 20;
The objective was to investigate if the hepatotoxic sensitivity in nonalcoholic steatohepatitic mice to acetaminophen (APAP) is due to downregulation of nuclear receptor PPARalpha via lower cell division and tissue repair. Male Swiss Webster mice fed methionine and choline deficient diet for 31 days exhibited NASH. On the 32nd day, a marginally toxic dose of APAP (360 mg/kg, ip) yielded 70% mortality in steatohepatitic mice, while all non steatohepatitic mice receiving the same dose survived. (14)C-APAP covalent binding, CYP2E1 protein, and enzyme activity did not differ from the controls, obviating increased APAP bioactivation as the cause of amplified APAP hepatotoxicity. Liver injury progressed only in steatohepatitic livers between 6 and 24 h. Cell division and tissue repair assessed by (3)H-thymidine incorporation and PCNA were inhibited only in the steatohepatitic mice given APAP suggesting that higher sensitivity of NASH liver to APAP-induced hepatotoxicity was due to lower tissue repair. The hypothesis that impeded liver tissue repair in steatohepatitic mice was due to downregulation of PPARalpha was tested. PPARalpha was downregulated in NASH. To investigate whether downregulation of PPARalpha in NASH is the critical mechanism of compromised liver tissue repair, PPARalpha was induced in steatohepatitic mice with clofibrate (250 mg/kg for 3 days, ip) before injecting APAP. All clofibrate pretreated steatohepatitic mice receiving APAP exhibited lower liver injury, which did not progress and the mice survived. The protection was not due to lower bioactivation of APAP but due to higher liver tissue repair. These findings suggest that inadequate PPARalpha expression in steatohepatitic mice sensitizes them to APAP hepatotoxicity. [PubMed Citation] [Order full text from Infotrieve]

4) Myers RP, Shaheen AA, Li B, Dean S, Quan H
Impact of Liver Disease, Alcohol Abuse, and Unintentional Ingestions on the Outcomes of Acetaminophen Overdose.
Clin Gastroenterol Hepatol. 2008 May 15;
BACKGROUND & AIMS: Acetaminophen overdose is the most common cause of acute liver failure in the U.S. and other Western countries. Unintentional overdoses, alcohol abuse, and underlying liver disease might increase the risk of hepatotoxicity. In this population-based study, we examined outcomes of acetaminophen overdose, with particular attention to these risk factors. METHODS: Patients hospitalized for acetaminophen overdose between 1995 and 2004 were identified retrospectively by using administrative data. Comorbid conditions, suicidal intent, and hepatotoxicity were identified by using International Classification of Diseases-Ninth Revision-Clinical Modification and International Statistical Classification of Diseases and Health-Related Problems, 10th revision diagnostic codes. RESULTS: During the 10-year interval, 1543 patients were hospitalized for acetaminophen overdose; 34% were alcohol abusers, 3% had liver disease, and 13% overdosed unintentionally. Seventy patients (4.5%) developed hepatotoxicity. Unintentional overdoses (odds ratio [OR], 5.18; 95% confidence interval [CI], 3.00-8.95), alcohol abuse (OR, 2.21; 95% CI, 1.30-3.76), underlying liver disease (OR, 3.50; 95% CI, 1.57-7.77), and N-acetylcysteine treatment (OR, 6.75; 95% CI, 2.78-16.39) were independently associated with hepatotoxicity. Fifteen patients (1.0%) died in-hospital; risk factors included older age, unintentional overdoses, alcohol abuse, comorbidities including liver disease, and hepatotoxicity (14% vs 0.3%; P < .0005). During a median follow-up of 5.2 years (range, 1 day-11.0 years), 79 patients (5.1%) died. Approximately half of these deaths were due to preventable conditions including suicide, substance abuse, and trauma. CONCLUSIONS: In this population-based study, acetaminophen overdose had a relatively benign short-term course but was associated with substantial long-term mortality caused by preventable conditions. Acetaminophen-related hepatotoxicity is more common in patients with unintentional overdoses, alcohol abuse, and underlying liver disease. [PubMed Citation] [Order full text from Infotrieve]

5) Jeong SY, Lim JS, Park HJ, Cho JW, Rana SV, Yoon S
Effects of acetaminophen on hepatic gene expression in mice.
Physiol Chem Phys Med NMR. 2006;38(2):77-83.
Acetaminophen (APAP) is one of the most commonly used drugs for the safe and effective treatment of fever and pain. However, it is a well-established hepatotoxin. The objective of this study was to identify alternation in various genes in liver of mice after administration of low and high doses of APAP. Male C57BL/6J mice received APAP (30 or 300 mg/kg, i.p.). They were sacrificed after 6 hr and 24 hr for assessment of alanine aminotransferase (ALT) and aspartate aminotransferase (AST), total RNA isolation, cDNA microarray analysis and histopathological analysis of liver injury. Low dose of APAP did not cause hepatotoxicity in mice. However, it was toxic at a high dose. Using microarray technology, we selected changed genes more than 1.5 fold. Gene expression changes were recorded even at a low dose treatment with APAP. Six (6) hr after APAP treatment at low dose, 6 genes were up-regulated and 25 genes were down-regulated. However, 24 hr after treatment at low dose 8 genes were up-regulated and 34 genes were down-regulated. 6 hr after of high dose treatment 29 genes were down-regulated and none was up-regulated. A 24 hr treatment with high dose up-regulated 6 genes and down-regulated 18 genes. These expression patterns provide information on high versus low dose mechanisms of APAP toxicity. Gene expression signatures recorded after a nontoxic dose of APAP strongly support the validity of gene expression changes as meaningful markers of hepatotoxicity. [PubMed Citation] [Order full text from Infotrieve]

6) Sun J, Schnackenberg LK, Holland RD, Schmitt TC, Cantor GH, Dragan YP, Beger RD
Metabonomics evaluation of urine from rats given acute and chronic doses of acetaminophen using NMR and UPLC/MS.
J Chromatogr B Analyt Technol Biomed Life Sci. 2008 Apr 12;
Urinary metabolic perturbations associated with acute and chronic acetaminophen-induced hepatotoxicity were investigated using nuclear magnetic resonance (NMR) spectroscopy and ultra performance liquid chromatography/mass spectrometry (UPLC/MS) metabonomics approaches to determine biomarkers of hepatotoxicity. Acute and chronic doses of acetaminophen (APAP) were administered to male Sprague-Dawley rats. NMR and UPLC/MS were able to detect both drug metabolites and endogenous metabolites simultaneously. The principal component analysis (PCA) of NMR or UPLC/MS spectra showed that metabolic changes observed in both acute and chronic dosing of acetaminophen were similar. Histopathology and clinical chemistry studies were performed and correlated well with the PCA analysis and magnitude of metabolite changes. Depletion of antioxidants (e.g. ferulic acid), trigonelline, S-adenosyl-l-methionine, and energy-related metabolites indicated that oxidative stress was caused by acute and chronic acetaminophen administration. Similar patterns of metabolic changes in response to acute or chronic dosing suggest similar detoxification and recovery mechanisms following APAP administration. [PubMed Citation] [Order full text from Infotrieve]

7) Bajt ML, Yan HM, Farhood A, Jaeschke H
PLASMINOGEN ACTIVATOR INHIBITOR-1 LIMITS LIVER INJURY AND FACILITATES REGENERATION AFTER ACETAMINOPHEN OVERDOSE.
Toxicol Sci. 2008 May 9;
Deficiency in plasminogen activator inhibitor-1 (PAI-1) gene expression is known to promote growth factor activation and regeneration in a number of hepatotoxicity models. To evaluate if PAI-1 has similar effects in acetaminophen (APAP) hepatotoxicity, wildtype and PAI-1 gene knockout mice (PAI-KO) were treated with 200 mg/kg APAP and liver injury and its repair were assessed. In wildtype animals, plasma alanine aminotransferase (ALT) activities increased during the first 12h and then returned to baseline within 48h. The area of necrosis increased in parallel to the ALT values, peaked between 12 and 24h and was completely resolved by 96h. The regenerative response of cells outside the necrotic area, as indicated by proliferating cell nuclear antigen (PCNA) protein and cyclin D(1) gene expression, was observed within 24h, peaked at 48h and then declined but remained elevated until 96h. Liver injury in response to APAP was similar in PAI-KO as in wildtype animals during the first 12h. However, plasma ALT values and the area of necrosis further increased during the following 12h with development of massive intrahepatic hemorrhage. Approximately 50% of the PAI-KO animals did not survive. Although liver injury of the surviving animals was repaired, the regeneration process was delayed until 48h. A potential reason for this delay may have been due to the more severe injury and/or the increased expression of the cell cycle inhibitor p27. Our data indicate that PAI activation limits liver injury and mortality during APAP hepatotoxicity by preventing excessive hemorrhage and thereby facilitating tissue repair. [PubMed Citation] [Order full text from Infotrieve]

8) Aleksunes LM, Campion SN, Goedken MJ, Manautou JE
Acquired Resistance to Acetaminophen Hepatotoxicity is Associated with Induction of Multidrug Resistance-Associated Protein 4 (Mrp4) in Proliferating Hepatocytes.
Toxicol Sci. 2008 May 8;
Treatment with hepatotoxicants such as acetaminophen (APAP) causes resistance to a second, higher dose of the same toxicant (autoprotection). APAP induces hepatic mRNA and protein levels of the multidrug resistance-associated proteins (Mrp) transporters in mice and humans. Basolateral efflux transporters Mrp3 and Mrp4 are the most significantly induced. We hypothesized that up-regulation of Mrp3 and Mrp4 is one mechanism by which hepatocytes become resistant to a subsequent higher dose of APAP by limiting accumulation of xeno-, endobiotics and byproducts of hepatocellular injury. The purpose of this study was to evaluate Mrp3 and Mrp4 expression in proliferating hepatocytes in a mouse model of APAP autoprotection. Plasma and livers were collected from male C57BL/6J mice treated with APAP 400 mg/kg for determination of hepatotoxicity and protein expression. Maximal Mrp3 and Mrp4 induction occurred 48 h after APAP. Mrp4 up-regulation occurred selectively in proliferating hepatocytes. Additional groups of APAP-pretreated mice were challenged 48 h later with a second, higher dose of APAP. APAP-pretreated mice had reduced hepatotoxicity after APAP challenge compared to those pretreated with vehicle. A more rapid recovery of glutathione in APAP-pretreated mice corresponded with increases in glutathione synthetic enzymes. Interestingly, mice pretreated and challenged with APAP had dramatic increases in Mrp4 expression as well as enhanced hepatocyte proliferation. Inhibition of hepatocyte replication with colchicine not only restored sensitivity of APAP-pretreated mice to injury, but also blocked Mrp4 induction. Mrp4 overexpression may be one phenotypic property of proliferating hepatocytes that protects against subsequent hepatotoxicant exposure by mechanisms that are presently unknown. [PubMed Citation] [Order full text from Infotrieve]

9) Grieco A, Miele L, Forgione A, Ragazzoni E, Vecchio FM, Gasbarrini G
Mild hepatitis at recommended doses of acetaminophen in patients with evidence of constitutionally enhanced cytochrome P450 system activity.
J Clin Pharm Ther. 2008 Jun;33(3):315-20.
Acetaminophen (paracetamol) is used throughout the world for pain relief and antipyresis in both children and adults. In many countries, it can be purchased without a medical prescription and it is also a common component of a number of over-the-counter remedies for colds, influenza and the like. Fasting, malnutrition and use of alcohol and/or other drugs are thought to play causal roles in hepatotoxicity associated with recommended doses of acetaminophen although liver injury provoked by therapeutic doses has also been observed in the absence of these factors. We describe two patients who experienced subclinical hepatotoxic reactions after taking acetaminophen at therapeutic doses. The results of an antipyrine metabolism test suggest the presence of constitutional hyperactivity of the cytochrome P450-dependent mixed function oxidative system in both patients. We hypothesize that the latter contributed to the hepatotoxicity and that it may play a role in idiosyncratic reactions to this drug. [PubMed Citation] [Order full text from Infotrieve]

10) Fontana RJ
Acute liver failure due to drugs.
Semin Liver Dis. 2008 May;28(2):175-87.
Acetaminophen overdose and idiosyncratic drug-induced liver injury (DILI) are the most commonly identified causes of acute liver failure (ALF) in the United States. Suspected acetaminophen hepatotoxicity can be effectively treated with N-acetylcysteine but still an estimated 500 patients die each year. Product labeling changes, dispensing restrictions, and reformulation of acetaminophen containing narcotic analgesics have been proposed to reduce the rising incidence of this preventable form of dose-dependent liver injury. In contrast, idiosyncratic DILI is not preventable due to our lack of understanding of host susceptibility and outcome factors. Patients with ALF due to DILI are difficult to diagnose and have a low likelihood of spontaneous recovery. Patients with severe idiosyncratic DILI should be urgently referred to a transplant center as there are no established medical treatments beyond drug discontinuation. Investigation of host variability in metabolic, regeneration, and immunological pathways may provide insights into the molecular basis of DILI as well as improved diagnostic and prognostic biomarkers. [PubMed Citation] [Order full text from Infotrieve]

11) Majlesi N, Greller HA, Su M, Chan GM
Comment on "Acute ethanol coingestion confers a lower risk of hepatotoxicity after deliberate acetaminophen overdose".
Acad Emerg Med. 2008 May;15(5):491-2; author reply 492.
[PubMed Citation] [Order full text from Infotrieve]

12) T J M, A K, O A, L N, J W, J P H
Cytochrome c: a non-invasive biomarker of drug-induced liver injury.
J Appl Toxicol. 2008 Apr 16;
Limitations of existing biomarkers to detect liver injury in experimental animals highlight the need for additional tools to predict human toxicity. The utility of cytochrome c (cyt c) as a biomarker in serum and urine was evaluated in two rodent liver injury models. Adult Sprague-Dawley rats treated with acetaminophen or d-galactosamine (GalN) showed dose- and time-dependent histomorphological changes and TUNEL staining in liver consistent with hepatocellular necrosis, apoptosis and inflammation up to 72 h. Matching changes in serum alanine transaminase (ALT), aspartate transaminase (AST) and cyt c peaked at 24 h for either drug at the highest dose, cyt c falling rapidly at 48 hours with ALT and AST remained high. Intracellular transit of cyt c from mitochondria to the cytoplasm in damaged hepatocytes, and then to peripheral circulation, was observed by immunohistochemistry. Correlation coefficients between cyt c and serum diagnostic tests indicate the liver to be the primary source of cyt c. Urinary analysis for cyt c revealed time-dependent increase at 6 h, peaking at 24 h in GalN-treated rats in contrast with irregular patterns of urinary ALT and AST activity. Histological changes detected at 6 h preceded altered ALT, AST and cyt c at 12 and 18 h, respectively, in GalN-treated rats. These studies demonstrate cyt c to be a useful indicator of hepatic injury in rodents and support its utility as a non-invasive predictor of drug-induced hepatotoxicity, when utilized as a potential urinary biomarker. Published in 2008 by John Wiley & Sons, Ltd. [PubMed Citation] [Order full text from Infotrieve]

13) Norris W, Paredes AH, Lewis JH
Drug-induced liver injury in 2007.
Curr Opin Gastroenterol. 2008 May;24(3):287-97.
PURPOSE OF REVIEW: To summarize the pertinent literature on the causes, epidemiology, prevalence, clinical features, evaluation and mechanisms of drug-induced liver injury reported during 2007. RECENT FINDINGS: Although the frequency of drug-induced liver injury remains low, new data from the Centers for Disease Control and Prevention confirm that of the approximately 1600 new acute liver failure cases annually, acetaminophen hepatotoxicity accounts for 41%; among children with acute liver failure, acetaminophen was the second most common cause. Antimicrobials lead the list of non-acetaminophen causes of drug-induced liver injury. In Asia, herbal compounds are the most common causes of the condition. Pravastatin was shown to be safe in patients with nonalcoholic fatty liver disease or chronic hepatitis C. The US Food and Drug Administration issued a draft guidance document on the premarketing clinical evaluation and stopping rules of drug-induced liver injury signals, including Hy's Law cases in clinical trials. SUMMARY: The year 2007 brought with it several reminders of the importance of drug-induced liver injury in the clinical trial as well as the clinical practice setting. There is additional evidence that statin drugs may be used safely in patients with chronic liver disease. Comments received by the US Food and Drug Administration to finalize their guidance document are eagerly awaited. [PubMed Citation] [Order full text from Infotrieve]

14) Bao XQ, Liu GT
Bicyclol: a novel antihepatitis drug with hepatic heat shock protein 27/70-inducing activity and cytoprotective effects in mice.
Cell Stress Chaperones. 2008 Apr 8;
Heat shock proteins (HSPs) are the best-known endogenous factors that protect against cell injury under various pathological conditions and that can be induced by various physical, chemical, and biological stressors. New research seeks to discover a compound that is clinically safe and can induce the accumulation of HSPs in patients. This paper reports that the oral administration of three doses of bicyclol, a novel antihepatitis drug, induced hepatic HSP27 and HSP70 expression in a time- and dose-dependent manner, and that bicyclol treatment stimulated heat shock factor 1 (HSF1) activation in mice. The inducing effects of bicyclol on HSP27, HSP70 and HSF1 were all blocked by quercetin, an inhibitor of HSP biosynthesis. The cytoprotective effect of HSP27/70 induced by bicyclol against hepatotoxicity of acetaminophen (AP) was assessed in mice. The prior administration of bicyclol markedly suppressed AP-induced liver injury as indicated by the reduction in the elevation of serum alanine aminotransferase and aspartate aminotransferase, in liver necrosis, in the release of cytochrome c and apoptosis-inducing factor from mitochondria, as well as in hepatic deoxyribonucleic acid fragmentation in mice. However, all the above actions of bicyclol against AP-induced mouse liver injuries were significantly attenuated by quercetin. This is the first report to show that bicyclol induces hepatic HSP27/70 expression via activation of HSF1 and that the cytoprotective action of bicyclol against liver injury is mediated by its induction of HSP27/70. These results provide new evidence for elucidating the mechanism of the hepatoprotective action of bicyclol in animals and patients. [PubMed Citation] [Order full text from Infotrieve]

15) Carey EJ, Vargas HE, Douglas DD, Balan V, Byrne TJ, Harrison ME, Rakela J
Inpatient Admissions for Drug-induced Liver Injury: Results from a Single Center.
Dig Dis Sci. 2008 Jul;53(7):1977-82.
Objective To review all cases of drug-induced liver injury (DILI) requiring hospitalization at a single tertiary care center. Methods Patient records were identified by ICD-9 codes for inpatient visits from November 1998 through March 2006. Results Of a total 83,265 hospital admissions during the study period, 40 were for DILI (0.048%). Thirteen patients had non-acetaminophen DILI (NA-DILI); 27 had acetaminophen-related DILI (A-DILI). In the NA-DILI group, mean age was 59 +/- 17.9 years and liver injury was classified as hepatocellular (7), cholestatic (5), or mixed (1). A variety of medications were implicated with antimicrobials being the most common class. Resolution occurred in seven, two died of complications related to hepatotoxicity, one underwent liver transplantation, and the outcome was undetermined in three who were lost to follow-up. In the A-DILI group, mean age was 35 +/- 11.0 years. Eighteen involved intentional overdose of acetaminophen; nine were associated with chronic use. The pattern of injury was hepatocellular in all. Resolution occurred in 4 patients, death in 8, and improvement in 15. Conclusions DILI is a rare cause of inpatient admission but is associated with significant mortality. Spontaneous resolution occurs in most patients but return to normal liver function may take months. Antimicrobial agents account for the largest proportion of NA-DILI. [PubMed Citation] [Order full text from Infotrieve]

16) Oz HS, Chen TS
Green-tea Polyphenols Downregulate Cyclooxygenase and Bcl-2 Activity in Acetaminophen-induced Hepatotoxicity.
Dig Dis Sci. 2008 Mar 29;
Acetaminophen (APAP) elicits hepatotoxicity via multifactorial pathways, including increased apoptosis, cyclooxygenase (Cox-2) generation, reactive metabolite release, and glutathione (GSH) depletion. We previously showed that mice that consumed different antioxidants in their diets were protected against APAP-induced hepatotoxicity. We therefore further investigated the mechanisms by which green-tea polyphenols (GrTP) protect against APAP-induced hepatic damage. Mice were administered a diet supplemented with GrTP or vehicle for 5 consecutive days followed by intraperitoneal (IP) injection of a toxic dose of APAP or sham. APAP administration upregulated Cox-2 and B-cell lymphoma-2 (Bcl-2) production and had an effect, albeit minor, on Cox-1 and Fas expression in hepatic tissue. GrTP supplementation normalized APAP induced Cox-2 expression and Bcl-2 activation (P < 0.01), as evidenced by immunohistochemistry and Western blot analyses. Similarly, APAP administration elicited marked depletion (99%) in hepatic reduced GSH (rGSH) and endogenous S-adenosylmethionine (SAMe) concentrations (twofold) when compared with sham. APAP also caused severe centrilobular apoptosis and necrosis accompanied by leukocyte infiltration and marked elevations in the hepatic enzyme, alanine aminotransferase (ALT) released from damaged hepatocytes, and cytokine tumor necrosis factor alpha (TNF-alpha). GrTP improved hepatic histopathology (P < 0.01) and attenuated ALT activity (P < 0.05) and the depletion of rGSH (P < 0.05). In conclusion, GrTP supplementation attenuated hepatotoxicity by normalizing Cox-2 and Bcl-2 activation, suggesting a potential use for GrTP in treatng APAP toxicity. [PubMed Citation] [Order full text from Infotrieve]

17) Ali FM, Boyer EW, Bird SB
Estimated risk of hepatotoxicity after an acute acetaminophen overdose in alcoholics.
Alcohol. 2008 May;42(3):213-8.
A published logistic regression model based on the Canadian Acetaminophen Overdose Study registry was used to calculate the risk of hepatotoxicity after an acute acetaminophen overdose and to estimate a treatment threshold line for alcoholic patients who did not co-ingest alcohol (i.e., abstinent alcoholics) on the Rumack-Matthew nomogram. The risk of hepatotoxicity in nonalcoholic and abstinent alcoholic patients was calculated at the acetaminophen concentration of 150 microg/ml at 4h (37.5 microg/ml at 12h) treatment threshold line. This corresponds to the "possible risk" line on the Rumack-Matthew nomogram and represents a 1.6% risk of hepatotoxicity for nonalcoholic patients at or below this line. At or below this same 150 microg/ml at 4-h line, abstinent alcoholic patients have a hepatotoxicity risk of 10.7%. The risk of hepatotoxicity in abstinent alcoholics' equivalent to that of nonalcoholics (i.e., 1.6%) occurs at a lower acetaminophen concentrations treatment threshold line, that is, 104 microg/ml at 4h (26 microg/ml at 12h). Because of difficulties plotting this new line on the familiar Rumack-Matthew semilogarithmic scale, a line connecting 100 microg/ml at 4h (25 microg/ml at 12h) is proposed. This line equates to a 1.1% risk of hepatotoxicity in abstinent alcoholic patients. The analysis supports the observation that based on the published model abstinent alcoholics might have a greater risk of hepatotoxicity after an acute acetaminophen overdose. This proposed new risk line can be used in hypothesis generation for future clinical studies in this alcohol related problem. [PubMed Citation] [Order full text from Infotrieve]

18) Jemnitz K, Veres Z, Monostory K, K�bori L, Vereczkey L
Interspecies differences in acetaminophen sensitivity of human, rat, and mouse primary hepatocytes.
Toxicol In Vitro. 2008 Jun;22(4):961-7.
Most of the experiments studying acetaminophen (APAP) induced hepatotoxicity were performed using moue as model specie, right because its high sensitivity. While the toxic responses can be called forth easily in mice, the human relevancy of these results is questionable. In this study human, rat, and mouse primary hepatocytes were treated with increasing concentrations of APAP, and cell viability was measured by MTT cytotoxicity assay. Pronounced interspecies differences were obtained in cell viability following 24h of APAP treatment starting at 24h after seeding (EC50: 3.8mM, 7.6mM, and 28.2mM, in mouse, rat, and human hepatocyte culture, respectively). The longer time of culturing highly increased the resistance of hepatocytes of all species investigated. In rat hepatocyte culture EC50 values were 6.0mM, 12.5mM, and 18.8mM, when starting APAP treatment after 24, 48, and 72 h of seeding. Although N-acetylbenzoquinoneimine, a minor metabolite of APAP, which is mainly formed by CYP2E1 at high APAP concentration in every species studied, is thought to initiate the toxic processes, no correlation was found between CYP2E1 activities and hepatocyte sensitivity of different species. We conclude that the toxicity induced by APAP overdose highly depends on the animal model applied. [PubMed Citation] [Order full text from Infotrieve]

19) Augusto O, Trindade DF, Linares E, Vaz SM
Cyclic nitroxides inhibit the toxicity of nitric oxide-derived oxidants: mechanisms and implications.
An Acad Bras Cienc. 2008 Mar;80(1):179-89.
The substantial therapeutic potential of tempol (4-hydroxy-2,2,6,6-tetramethyl-1-piperidinyloxy) and related cyclic nitroxides as antioxidants has stimulated innumerous studies of their reactions with reactive oxygen species. In comparison, reactions of nitroxides with nitric oxide-derived oxidants have been less frequently investigated. Nevertheless, this is relevant because tempol has also been shown to protect animals from injuries associated with inflammatory conditions, which are characterized by the increased production of nitric oxide and its derived oxidants. Here, we review recent studies addressing the mechanisms by which cyclic nitroxides attenuate the toxicity of nitric oxide derived oxidants. As an example, we present data showing that tempol protects mice from acetaminophen-induced hepatotoxicity and discuss the possible protection mechanism. In view of the summarized studies, it is proposed that nitroxides attenuate tissue injury under inflammatory conditions mainly because of their ability to react rapidly with nitrogen dioxide and carbonate radical. In the process the nitroxides are oxidized to the corresponding oxammonium cation, which, in turn, can be recycled back to the nitroxides by reacting with upstream species, such as peroxynitrite and hydrogen peroxide, or with cellular reductants. An auxiliary protection mechanism may be down-regulation of inducible nitric oxide synthase expression. The possible therapeutic implications of these mechanisms are addressed. [Free Full Text] [PubMed Citation] [Order full text from Infotrieve]

20) Bartels S, Sivilotti M, Crosby D, Richard J
Are recommended doses of acetaminophen hepatotoxic for recently abstinent alcoholics? A randomized trial.
Clin Toxicol (Phila). 2008 Mar;46(3):243-9.
Although acetaminophen overdose is a leading cause of fulminant hepatic failure, it is controversial whether therapeutic doses of acetaminophen can cause hepatotoxicity in alcoholics, especially those rendered most vulnerable by recent abstinence. We performed a randomized, triple-blind, parallel-group trial comparing sustained-release acetaminophen, 1300 mg orally q8h for 11 doses, against placebo. We enrolled chronic alcohol abusers (defined as >or= 6 drinks daily for >or= 6 weeks) who had discontinued alcohol consumption 12 to 72 hours prior to enrollment. Individuals with self-reported viral hepatitis, HIV or intravenous drug use, baseline AST or ALT >120 IU/L, or INR >1.5 were excluded. Hepatic function tests were drawn daily for 5 days. The primary outcome was change in serum alpha-GST, a sensitive experimental biomarker of hepatocellular injury; secondary outcomes were changes in serum AST, ALT, INR, and study withdrawal for a doubling of aminotransferases to >120 IU/L. Of 52 subjects randomized, 40 completed at least four days of intervention. Subjects receiving acetaminophen had 32% [95% CI 7%, 50%] and 29% [6%, 46%] lower serum alpha-GST concentrations on days 2 and 3, respectively, compared to placebo, but these differences disappeared by day 4. No subjects were withdrawn for safety reasons. In conclusion, therapeutic doses of sustained-release acetaminophen cause a measurable decrease in serum alpha-GST during the first days of abstinence from chronic alcohol use. While the mechanism is unclear, these observations do provide some reassurance that short courses of acetaminophen are unlikely to cause subclinical hepatocellular injury in recently abstinent alcoholics. [PubMed Citation] [Order full text from Infotrieve]