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) Sharma S, Chaturvedi J, Chaudhari BP, Singh RL, Kakkar P
Probiotic Enterococcus lactis IITRHR1 protects against acetaminophen-induced hepatotoxicity.
Nutrition. 2011 Jul 19;
OBJECTIVE: Acetaminophen (APAP), an antipyretic/analgesic drug, is reported to cause toxicity on overdose. Dietary supplements are currently being explored to decrease toxicity. In the present study, the protective effect of probiotic Enterococcus lactis IITRHR1 was evaluated at different doses (10(7), 10(8), and 10(9) colony-forming units) against APAP-induced liver damage. METHODS: Male Wistar rats were administered APAP (1 g/kg of body weight orally) for 14 d, and hepatotoxicity was assessed by marker enzymes in serum and observation of histopathologic changes. Rats were pretreated with probiotic E. lactis IITRHR1 for 7 d and modulation of antioxidant enzymes (superoxide dismutase, catalase, glutathione peroxidase, glutathione-S-transferase), redox ratio, and ferric reducing antioxidant power was assessed. Oxidative damage by APAP to membrane lipids, proteins, and DNA was also observed. Involvement of Bax, Bcl2, cytochrome c (pro-/anti-apoptotic proteins), caspases, and their modulation was assessed by immunoblot analysis and reverse transcriptase polymerase chain reaction. RESULTS: The E. lactis IITRHR1 pretreatment lowered the level of biomarkers of hepatotoxicity in serum. A significant increase was observed in the level of antioxidant enzymes and redox ratio and decreased oxidative damage to membrane lipids and proteins. Probiotic E. lactis IITRHR1 also modulated key apoptotic/anti-apoptotic proteins such as cytochrome-c, Bcl2, Bax, expression of caspases, and resultant DNA damage. CONCLUSION: Probiotic strain E. lactis IITRHR1 was found to have antioxidant capacity and afforded protection against APAP-induced hepatotoxicity by modulating antioxidant status, pro-/anti-apoptotic proteins, caspases, and DNA damage. [PubMed Citation] [Order full text from Infotrieve]

2) Jain NK, Singhai AK
Protective effects of Phyllanthus acidus (L.) Skeels leaf extracts on acetaminophen and thioacetamide induced hepatic injuries in Wistar rats.
Asian Pac J Trop Med. 2011 Jun;4(6):470-4.
[PubMed Citation] [Order full text from Infotrieve]

3) Geenen S, Guallar-Hoyas C, Michopoulos F, Kenna JG, Kolaja KL, Westerhoff HV, Thomas P, Wilson ID
HPLC-MS/MS methods for the quantitative analysis of 5-oxoproline (pyroglutamate) in rat plasma and hepatic cell line culture medium.
J Pharm Biomed Anal. 2011 Jun 13;
5-Oxoproline (5-OP; pyroglutamate) is an intermediate in the biosynthesis of the endogenous tripeptide glutathione and has been seen to be elevated in the biofluids and tissues of rats following the administration of glutathione-depleting hepatotoxic xenobiotics such as acetaminophen (paracetamol), bromobenzene and ethionine. As 5-OP is a potential biomarker for hepatotoxicity HPLC-MS/MS methods have been developed for its quantification in in vitro cell culture media and rat plasma. For the cell culture media the lower limit of quantification (LLOQ), defined as the lowest concentration on the calibration curve, was 10ng/ml. Minimal carry over was observed for cell culture media between injections (less than 5% at all concentrations examined), precision and accuracy were generally better than 20% for within and between day analyses. For rat plasma a LLOQ of 50ng/ml was obtained. Carry over for plasma was less than 5% for all concentrations, within and between batch accuracy and precision were generally better than 20%. The methods were linear for both sample types from the LLOQ up to 1?g/ml. For samples obtained from rats subjected to chronic administration of the hepatotoxin methapyrilene, concentrations of 5-OP were not observed to increase significantly at any time point compared to controls. 5-OP was also determined in the culture media of human liver epithelial (THLE) cells transfected with cytochrome P450 2E1 (THLE-2E1). Following exposure of THLE-2E1 cells to acetaminophen, large increases in the concentrations of 5-OP were observed, which correlated with reduced cellular glutathione content and with cell toxicity. These results show that LC-MS/MS can be used to perform rapid, sensitive, and quantitative determination of 5-OP in vivo and in vitro and will enable additional investigations into the utility of 5-OP as a biomarker of liver drug-induced liver injury. [PubMed Citation] [Order full text from Infotrieve]

4) Jaeschke H, Williams CD, Ramachandran A, Bajt ML
Acetaminophen hepatotoxicity and repair: the role of sterile inflammation and innate immunity.
Liver Int. 2011 Mar 14;
Acetaminophen (APAP) hepatotoxicity because of overdose is the most frequent cause of acute liver failure in the western world. Metabolic activation of APAP and protein adduct formation, mitochondrial dysfunction, oxidant stress, peroxynitrite formation and nuclear DNA fragmentation are critical intracellular events in hepatocytes. However, the early cell necrosis causes the release of a number of mediators such as high-mobility group box 1 protein, DNA fragments, heat shock proteins (HSPs) and others (collectively named damage-associated molecular patterns), which can be recognized by toll-like receptors on macrophages, and leads to their activation with cytokine and chemokine formation. Although pro-inflammatory mediators recruit inflammatory cells (neutrophils, monocytes) into the liver, neither the infiltrating cells nor the activated resident macrophages cause any direct cytotoxicity. In contrast, pro- and anti-inflammatory cytokines and chemokines can directly promote intracellular injury mechanisms by inducing nitric oxide synthase or inhibit cell death mechanisms by the expression of acute-phase proteins (HSPs, heme oxygenase-1) and promote hepatocyte proliferation. In addition, the newly recruited macrophages (M2) and potentially neutrophils are involved in the removal of necrotic cell debris in preparation for tissue repair and resolution of the inflammatory response. Thus, as discussed in detail in this review, the preponderance of experimental evidence suggests that the extensive sterile inflammatory response during APAP hepatotoxicity is predominantly beneficial by limiting the formation and the impact of pro-inflammatory mediators and by promoting tissue repair. [PubMed Citation] [Order full text from Infotrieve]

5) Clement C, Scala-Bertola J, Javot L, Royer-Morrot MJ, Gillet P, Trechot P, Petitpain N, Gambier N
Misuse of acetaminophen in the management of dental pain.
Pharmacoepidemiol Drug Saf. 2011 Jul 1;
PURPOSE: We highlight the risk associated with acetaminophen misuse in patients having dental pain in France based on a series of cases of unintentional acetaminophen overdose reported by the Emergency Dental Service of Nancy over a 9-month period. METHODS: Data were collected by querying the French Pharmacovigilance database. Each retrieved clinical data were reviewed by a clinician. RESULTS: Thirteen cases of acetaminophen overdose were reported to the Regional Pharmacovigilance Center of Lorraine, Nancy, France. Most cases (10/13) concerned men aged 20-40?years old. Mild, unspecific clinical symptoms were observed in seven of 13 patients. The median value of the supposed ingested dose was 137?mg/kg/24?h. Liver enzyme activity was tested in 10 patients and was abnormal in four patients. N-acetylcysteine treatment was administered to four patients. CONCLUSIONS: We propose that even patients with mild clinical symptoms with a supposed ingested dose of acetaminophen greater than 150?mg/kg/24?h should be referred to an emergency department and that liver enzyme activity should be analyzed. No case of liver failure was observed during our short survey. However, hepatotoxicity of repeated supratherapeutic ingestion of acetaminophen was suspected in four patients. Patients and practitioners should thus be better informed about the risk of unintentional acetaminophen overdose following supratherapeutic acetaminophen ingestion. Copyright � 2011 John Wiley & Sons, Ltd. [PubMed Citation] [Order full text from Infotrieve]

6) Lu Z, Bourdi M, Li JH, Aponte AM, Chen Y, Lombard DB, Gucek M, Pohl LR, Sack MN
SIRT3-dependent deacetylation exacerbates acetaminophen hepatotoxicity.
EMBO Rep. 2011 Jul 1;
Acetaminophen/paracetamol-induced liver failure-which is induced by the binding of reactive metabolites to mitochondrial proteins and their disruption-is exacerbated by fasting. As fasting promotes SIRT3-mediated mitochondrial-protein deacetylation and acetaminophen metabolites bind to lysine residues, we investigated whether deacetylation predisposes mice to toxic metabolite-mediated disruption of mitochondrial proteins. We show that mitochondrial deacetylase SIRT3(-/-) mice are protected from acetaminophen hepatotoxicity, that mitochondrial aldehyde dehydrogenase 2 is a direct SIRT3 substrate, and that its deacetylation increases acetaminophen toxic-metabolite binding and enzyme inactivation. Thus, protein deacetylation enhances xenobiotic liver injury by modulating the binding of a toxic metabolite to mitochondrial proteins. [PubMed Citation] [Order full text from Infotrieve]

7) Dougherty PP, Klein-Schwartz W
Unexpected Late Rise in Plasma Acetaminophen Concentrations with Change in Risk Stratification in Acute Acetaminophen Overdoses.
J Emerg Med. 2011 Jun 28;
BACKGROUND: The acetaminophen risk analysis nomogram is used to predict hepatotoxicity risk in acute acetaminophen overdose based on a single plasma acetaminophen concentration (PAC) measured between 4 and 24 h after ingestion. There are case reports of patients with acute overdoses of acetaminophen combination products in whom a toxic PAC occurred later after an initial non-toxic PAC at approximately 4 h. OBJECTIVES: The objective was to describe patients who had an initial non-toxic PAC and a subsequent toxic PAC. METHODS: A poison center's database was searched for records in which patients were administered N-acetylcysteine. Cases were included if they involved an acute overdose of an acetaminophen-containing product with at least 2 plottable PACs, the first of which was obtained at least 4 h after ingestion and was below the treatment line on the nomogram with a subsequent toxic PAC. Data were analyzed for doses, timed PACs, specific acetaminophen preparation, coingestants, activated charcoal administration, and clinical effects. RESULTS: Twenty patients were included. Thirteen patients ingested combination products. All patients experienced vomiting, neurologic, or cardiovascular effects at presentation or before obtaining the second PAC. Two patients developed hepatotoxicity, one of which died�from the complications of acetaminophen-induced hepatotoxicity. CONCLUSION: The nomogram fails to predict toxicity based on a single PAC in a small subset of patients. [PubMed Citation] [Order full text from Infotrieve]

8) Ahmed MM, Wang T, Luo Y, Ye S, Wu Q, Guo Z, Roebuck BD, Sutter TR, Yang JY
Aldo-keto reductase-7A protects liver cells and tissues from acetaminophen-induced oxidative stress and hepatotoxicity.
Hepatology. 2011 Jun 17;
Aldo-keto reductase-7A (AKR7A) is an enzyme important for bioactivation and biodetoxification. Previous studies suggested that Akr7a might be transcriptionally regulated by oxidative stress-responsive transcription factor Nrf2, a protein highly responsive to acetaminophen (APAP) or its intermediate metabolite N-acetyl-p-benzoquinoneimine (NAPQI). This study was therefore carried out to investigate whether Akr7a is involved in the protection against APAP-induced oxidative stress and hepatotoxicity. We found that in response to APAP or NAPQI exposure, Akr7a3 mRNA and protein were significantly up-regulated in vitro in human HepG2 and LO2 cells. Similarly, strong induction was observed for Akr7a5 in mouse AML12 hepatocytes exposed to APAP. In vivo in wildtype rats, significant up-regulation of hepatic AKR7A1 protein was observed following administration of APAP. On the other hand, depletion of Nrf2 reduced the expression of Akr7a3, suggesting that Nrf2 indeed contributes significantly to the induction of Akr7a. Moreover, loss of cell viability in Nrf2-depleted cells was significantly rescued by co-expression of AKR7A3. Further, increased AKR7A3 in HepG2 cells was associated with the up-regulation of oxidative stress-related enzymes to enhance cellular antioxidant defense, which appeared to contribute significantly to the protection against APAP-induced toxicity. In a line of transgenic rats overexpressing AKR7A1, increased AKR7A1 stimulated the expression of Nrf2 and other Nrf2-regulated genes, but did not better protect rats from APAP insults. In contrast, depletion of Akr7a5 in vitro in cultured AML12 cells or depletion of Akr7a1 in vivo in rat liver greatly increased APAP-induced hepatotoxicity. Conclusion: AKR7A proteins are significantly up-regulated in response to APAP/NAPQI exposure to contribute significantly to the protection against APAP-induced hepatotoxicity. AKR7A mediates the protection in part through enhancing hepatocellular antioxidant defense. (HEPATOLOGY 2011.). [PubMed Citation] [Order full text from Infotrieve]

9) He YY, Zhang BX, Jia FL
Protective effects of 2,4-dihydroxybenzophenone against acetaminophen-induced hepatotoxicity in mice.
World J Gastroenterol. 2011 Jun 7;17(21):2663-6.
[PubMed Citation] [Order full text from Infotrieve]

10) Schutte M, Fox B, Baradez MO, Devonshire A, Minguez J, Bokhari M, Przyborski S, Marshall D
Rat Primary Hepatocytes Show Enhanced Performance and Sensitivity to Acetaminophen During Three-Dimensional Culture on a Polystyrene Scaffold Designed for Routine Use.
Assay Drug Dev Technol. 2011 Jun 15;
Abstract The in vitro evaluation of hepatotoxicity is an essential stage in the research and development of new pharmaceuticals as the liver is one of the most commonly impacted organs during preclinical toxicity studies. Fresh primary hepatocytes in monolayer culture are the most commonly used in vitro model of the liver but often exhibit limited viability and/or reduction or loss of important liver-specific functions. These limitations could potentially be overcome using three-dimensional (3D) culture systems, but their experimental nature and limited use in liver toxicity screening and drug metabolism has impaired their uptake into commercial screening programs. In this study we use a commercially available polystyrene scaffold developed for routine 3D cell culture to maintain primary rat hepatocytes for use in metabolism and toxicity studies over 72?h. We show that primary hepatocytes retain their natural cuboidal morphology with significantly higher viability (>74%) than cells grown in monolayer culture (maximum of 57%). Hepatocytes in the 3D scaffolds exhibit differential expression of genes associated with phase I, II, and III drug metabolism under basal conditions compared with monolayer culture and can be induced to stably express significantly higher levels of the cytochrome-P450 enzymes 1A2, 2B1, and 3A2 over 48?h. In toxicity studies the hepatocytes in the 3D scaffolds also show increased sensitivity to the model toxicant acetaminophen. These improvements over monolayer culture and the availability of this new easy to use 3D scaffold system could facilitate the uptake of 3D technologies into routine drug screening programs. [PubMed Citation] [Order full text from Infotrieve]

11) Masubuchi Y, Nakayama J, Watanabe Y
Sex difference in susceptibility to acetaminophen hepatotoxicity is reversed by buthionine sulfoximine.
Toxicology. 2011 Jun 6;
Gender is a factor that influences susceptibility of individuals to drug-induced liver injury in experimental animals and humans. In this study, we investigated the mechanisms underlying resistance of female mice to acetaminophen (APAP)-induced hepatotoxicity. Overnight-fasted male and female CD-1 mice were administered APAP intraperitoneally. A minor increase in serum alanine aminotransferase levels was observed in female mice after APAP administration at a dose that causes severe hepatotoxicity in males. Hepatic glutathione (GSH) depleted rapidly in the both genders prior to development of hepatotoxicity, whereas its recovery was more rapid in female than in male mice. This was consistent with higher induction of hepatic glutamate-cysteine ligase (GCL) in females. Pretreatment of mice with L-buthionine sulfoximine (BSO), an inhibitor of GCL, exaggerated APAP hepatotoxicity only in female mice, resulting in much higher hepatotoxicity in female than in male mice. In addition, hepatic GSH was markedly depleted in BSO-pretreated female mice compared with male mice, which supports severe hepatotoxicity in BSO-pretreated females. APAP treatment highly induced multidrug resistance-associated protein 4 (Mrp4) only in female mice. The resulting high Mrp4 expression could thus contribute to decreased hepatic GSH levels via sinusoidal efflux when GCL is inhibited. In conclusion, resistance to APAP hepatotoxicity in female mice and its reversal by pretreatment with BSO could be attributed to sex differences in disposition of hepatic GSH, which may generally determine susceptibility to drug-induced liver injury. [PubMed Citation] [Order full text from Infotrieve]

12) Fukuhara K, Ohno A, Ando Y, Yamoto T, Okuda H
A 1H NMR-Based Metabolomics Approach for Mechanistic Insight into Acetaminophen Induced Hepatotoxicity.
Drug Metab Pharmacokinet. 2011 Jun 14;
The widely used analgesic-antipyretic drug acetaminophen (APAP) is known to cause serious liver necrosis at high doses in man and experimental animals. For studies of toxic processes, 1H NMR spectroscopy of biofluids allows monitoring of endogenous metabolite profiles that alter characteristically in response to changes in physiological status. Herein, a 1H NMR metabolomics approach was applied to the investigation of APAP toxicity in rats and the effect of phenobarbital (PB) on APAP induced hepatotoxicity. Metabolite differences due to hepatotoxicity were observed in 1H NMR spectra of serum and urine, and enhanced APAP hepatotoxicity by pretreatment with PB was clearly shown by a principal components analysis of the spectral data. NMR spectra of APAP dosed rat urine provided profiles of APAP-related compounds together with endogenous metabolites. By comparison of endogenous and APAP-related metabolite spectra with those from rats pretreated with PB, it was possible to show the importance of oxidative metabolism of APAP to N-acetyl-p-benzoquinone, an essential component of APAP hepatotoxicity. [PubMed Citation] [Order full text from Infotrieve]

13) Loguidice A, Boelsterli UA
Acetaminophen overdose-induced liver injury in mice is mediated by peroxynitrite independently of the cyclophilin D-regulated Permeability transition.
Hepatology. 2011 May 29;
Acetaminophen (APAP) is safe at therapeutic dosage but can cause severe hepatotoxicity if used at overdose. The mechanisms of injury are not yet fully understood, but previous reports had suggested that the mitochondrial permeability transition (mPT) may be involved in triggering hepatocellular necrosis. We aimed at inhibiting mitochondrial cyclophilin D (CypD), a key regulator of the mPT, as a potential therapeutic target in APAP hepatotoxicity. Wild-type mice treated with a high dose of APAP (600 mg/kg, ip) developed typical centrilobular necrosis, which could, however, not be prevented by co-treatment with the selective CypD inhibitor, Debio 025 (alisporivir, DEB025, a non-immunosuppressive cyclosporin A analog). Similarly, genetic ablation of mitochondrial CypD in Ppif-null mice did not afford protection from APAP hepatotoxicity. To determine whether APAP-induced peroxynitrite stress might directly activate mitochondrial permeabilization, independently of the CypD-regulated mPT, we co-administered the peroxynitrite decomposition catalyst Fe-TMPyP (10 mg/kg, ip, 90 min prior to APAP) to CypD-deficient mice. Liver injury was greatly attenuated by Fe-TMPyP pretreatment, and mitochondrial 3-nitrotyrosine adduct levels (peroxynitrite marker) were decreased. Acetaminophen treatment increased both the cytosolic and mitochondria-associated P-JNK levels, but the JNK signaling inhibitor SP600125 was hepatoprotective in wild-type mice only, indicating that the JNK pathway may not be critically involved in the absence of CypD. Conclusion: These data support the concept that an overdose of APAP results in liver injury via a peroxynitrite-mediated mode of cell death signaling that is distinct from the mitochondrial CypD-regulated mPT and that is refractory to pharmacological inhibition or genetic depletion of CypD. (HEPATOLOGY 2011.). [PubMed Citation] [Order full text from Infotrieve]

14) Li X, Kondoh M, Watari A, Hasezaki T, Isoda K, Tsutsumi Y, Yagi K
Effect of 70-nm silica particles on the toxicity of acetaminophen, tetracycline, trazodone, and 5-aminosalicylic acid in mice.
Pharmazie. 2011 Apr;66(4):282-6.
Exposure to nano-sized particles is increasing because they are used in a wide variety of industrial products, cosmetics, and pharmaceuticals. Some animal studies indicate that such nanomaterials may have some toxicity, but their synergistic actions on the adverse effects of drugs are not well understood. In this study, we investigated whether 70-nm silica particles (nSP70), which are widely used in cosmetics and drug delivery, affect the toxicity of a drug for inflammatory bowel disease (5-aminosalicylic acid), an antibiotic drug (tetracycline), an antidepressant drug (trazodone), and an antipyretic drug (acetaminophen) in mice. Co-administration of nSP70 with trazodone did not increase a biochemical marker of liver injury. In contrast, co-administration increased the hepatotoxicity of the other drugs. Co-administration of nSP70 and tetracycline was lethal. These findings indicate that evaluation of synergistic adverse effects is important for the application of nano-sized materials. [PubMed Citation] [Order full text from Infotrieve]

15) Rangnekar A, Fontana R
An update on drug induced liver injury.
Minerva Gastroenterol Dietol. 2011 Jun;57(2):213-29.
Drug induced liver injury (DILI) is an uncommon cause of acute and chronic liver injury of increasing importance to patients, clinicians, and regulators. The incidence of DILI due to an individual agent is not well defined but population-based studies suggest that the overall incidence of DILI may be as high as 10 to 15 cases per 100�000 patient years. Bona fide risk factors for DILI are also not well established, but ongoing multicenter registry studies such as the Drug Induced Liver Injury Network are attempting to identify the role of genetic, environmental, and immunological factors in DILI pathogenesis and outcomes. Acute hepatocellular injury (~50%) is more common than mixed or cholestatic liver injury but jaundiced DILI subjects with either type of liver injury have a ~10% risk of short-term mortality. Antibiotics are the most commonly implicated agents associated with DILI, but there are emerging reports of liver injury associated with the use of a multitude of herbal and dietary supplements. Despite their widespread use, the HMG-CoA reductase inhibitors or statins are an uncommon cause of idiosyncratic DILI. Furthermore, recent studies have shown that statins are actually safe and efficacious to use in hyperlipidemic patients with chronic liver disease. Acetaminophen hepatotoxicity remains a leading cause of severe acute liver injury. Limiting the amount of acetaminophen in prescription narcotic products may help reduce the incidence of future non-intentional overdoses but educating patients and providers of the multitude of over the counter products that contain acetaminophen is also recommended. [PubMed Citation] [Order full text from Infotrieve]

16) Johnson MT, McCammon CA, Mullins ME, Halcomb SE
Evaluation of a simplified N-acetylcysteine dosing regimen for the treatment of acetaminophen toxicity.
Ann Pharmacother. 2011 Jun;45(6):713-20.
[PubMed Citation] [Order full text from Infotrieve]

17) Sparkenbaugh EM, Saini Y, Greenwood KK, Lapres JJ, Luyendyk JP, Copple BL, Maddox JF, Ganey PE, Roth RA
The Role of Hypoxia-Inducible Factor-1{alpha} in Acetaminophen Hepatotoxicity.
J Pharmacol Exp Ther. 2011 Aug;338(2):492-502.
Hypoxia-inducible factor-1? (HIF-1?) is a critical transcription factor that controls oxygen homeostasis in response to hypoxia, inflammation, and oxidative stress. HIF has been implicated in the pathogenesis of liver injury in which these events play a role, including acetaminophen (APAP) overdose, which is the leading cause of acute liver failure in the United States. APAP overdose has been reported to activate HIF-1? in mouse livers and isolated hepatocytes downstream of oxidative stress. HIF-1? signaling controls many factors that contribute to APAP hepatotoxicity, including mitochondrial cell death, inflammation, and hemostasis. Therefore, we tested the hypothesis that HIF-1? contributes to APAP hepatotoxicity. Conditional HIF-1? deletion was generated in mice using an inducible Cre-lox system. Control (HIF-1?-sufficient) mice developed severe liver injury 6 and 24 h after APAP overdose (400 mg/kg). HIF-1?-deficient mice were protected from APAP hepatotoxicity at 6 h, but developed severe liver injury by 24 h, suggesting that HIF-1? is involved in the early stage of APAP toxicity. In further studies, HIF-1?-deficient mice had attenuated thrombin generation and reduced plasminogen activator inhibitor-1 production compared with control mice, indicating that HIF-1? signaling contributes to hemostasis in APAP hepatotoxicity. Finally, HIF-1?-deficient animals had decreased hepatic neutrophil accumulation and plasma concentrations of interleukin-6, keratinocyte chemoattractant, and regulated upon activation normal T cell expressed and secreted compared with control mice, suggesting an altered inflammatory response. HIF-1? contributes to hemostasis, sterile inflammation, and early hepatocellular necrosis during the pathogenesis of APAP toxicity. [PubMed Citation] [Order full text from Infotrieve]

18) Connolly MK, Ayo D, Malhotra A, Hackman M, Bedrosian AS, Ibrahim J, Cieza-Rubio NE, Nguyen AH, Henning JR, Dorvil-Castro M, Pachter HL, Miller G
Dendritic cell depletion exacerbates acetaminophen hepatotoxicity.
Hepatology. 2011 May 13;
Acetaminophen (APAP) overdose is one of the most frequent causes of acute liver failure in the United States and is primarily mediated by toxic metabolites which accumulate in the liver upon depletion of glutathione stores. However, cells of the innate immune system, including NK cells, neutrophils, and Kupffer cells, have also been implicated in the centrilobular liver necrosis associated with APAP. We have recently shown that dendritic cells (DC) regulate intra-hepatic inflammation in chronic liver disease and, therefore, postulated that DC may also modulate the hepatotoxic effects of APAP. We found that DC immune-phenotype was markedly altered after APAP challenge. In particular, liver DC expressed higher MHC II, co-stimulatory molecules, and Toll-like Receptors, and produced higher IL-6, MCP-1, and TNF-?. Conversely, spleen DC were unaltered. However, APAP-induced centrilobular necrosis, and its associated mortality, was markedly exacerbated upon DC depletion. Conversely, endogenous DC expansion using FMS-like tyrosine kinase 3 ligand (Flt3L) protected mice from APAP injury. Our mechanistic studies showed that APAP liver DC had the particular capacity to prevent NK cell activation and induced neutrophil apoptosis. Nevertheless, the exacerbated hepatic injury in DC depleted mice challenged with APAP was independent of NK cells and neutrophils or numerous immune modulatory cytokines and chemokines. Conclusions: Taken together, these data indicate that liver DC protect against APAP toxicity while their depletion is associated with exacerbated hepatotoxicity. (HEPATOLOGY 2011.). [PubMed Citation] [Order full text from Infotrieve]

19) Bajt ML, Ramachandran A, Yan HM, Lebofsky M, Farhood A, Lemasters JJ, Jaeschke H
Apoptosis-Inducing Factor Modulates Mitochondrial Oxidant Stress in Acetaminophen Hepatotoxicity.
Toxicol Sci. 2011 May 13;
Acetaminophen (APAP) overdose causes liver injury in humans and mice. DNA fragmentation is a hallmark of APAP-induced cell death and nuclear translocation of apoptosis-inducing factor (AIF) correlates with DNA fragmentation after APAP overdose. To test the hypothesis that AIF may be a critical mediator of APAP-induced cell death, fasted male AIF-deficient (Hq) mice and respective wild type (WT) animals were treated with 200 mg/kg APAP. At 6h after APAP, WT animals developed severe liver injury as indicated by the increase in plasma ALT activities (8600�1870 U/L) and 61�8% necrosis. This injury was accompanied by massive DNA strand breaks in centrilobular hepatocytes (TUNEL assay) and release of DNA fragments into the cytosol (anti-histone ELISA). In addition, there was formation of reactive oxygen (increase in liver glutathione disulfide levels and mitochondrial protein carbonyls) and peroxynitrite (nitrotyrosine staining) together with mitochondrial translocation of activated c-jun-N-terminal kinase (P-JNK) and release of AIF from the mitochondria. In contrast, Harlequin (Hq) mice had significantly less liver injury (ALT: 330�130 U/L; necrosis: 4�2%), minimal nuclear DNA damage and drastically reduced oxidant stress (based on all parameters) at 6h. WT and Hq mice had the same baseline levels of cyp2E1 and of glutathione. The initial depletion of glutathione (20 min after APAP) was the same in both groups suggesting that there was no relevant difference in metabolic activation of APAP. Thus, AIF has a critical function in APAP hepatotoxicity by facilitating generation of reactive oxygen in mitochondria and, after nuclear translocation, AIF can be involved in DNA fragmentation. [PubMed Citation] [Order full text from Infotrieve]

20) Radosavljević T, Mladenović D, Vucević D, Vukićević RJ
[The role of oxidative/nitrosative stress in pathogenesis of paracetamol-induced toxic hepatitis].
Med Pregl. 2010 Nov-Dec;63(11-12):827-32.
INTRODUCTION: Paracetamol is an effective analgesic/antipyretic drug when used at therapeutic doses. However, the overdose of paracetamol can cause severe liver injury and liver necrosis. The mechanism of paracetamol-induced liver injury is still not completely understood. Reactive metabolite formation, depletion of glutathione and alkylation of proteins are the triggers of inhibition of mitochondrial respiration, adenosine triphosphate depletion and mitochondrial oxidant stress leading to hepatocellular necrosis. ROLE OF OXIDATIVE STRESS IN PARACETAMOL-INDUCED LIVER INJURY: The importance of oxidative stress in paracetamol hepatotoxicity is controversial. Paracetamol-induced liver injury cause the formation of reactive oxygen species. The potent sources of reactive oxygen are mitochondria, neutrophils. Kupffer cells and the enzyme xatnine oxidase. Free radicals lead to lipid peroxidation, enzymatic inactivation and protein oxidation. ROLE OF MITOCHONDRIA IN PARACETAMOL-INDUCED OXIDATIVE STRESS: The production of mitochondrial reactive oxygen species is increased, and the glutathione content is decreased in paracetamol overdose. Oxidative stress in mitochondria leads to mitochondrial dysfunction with adenosine triphosphate depletion, increase mitochondrial permeability transition, deoxyribonucleic acid fragmentation which contribute to the development of hepatocellular necrosis in the liver after paracetamol overdose. ROLE OF KUPFFER CELLS IN PARACETAMOL-INDUCED LIVER INJURY: Paracetamol activates Kupffer cells, which then release numerous cytokines and signalling molecules, including nitric oxide and superoxide. Kupffer cells are important in peroxynitrite formation. On the other hand, the activated Kupffer cells release anti-inflammatory cytokines. ROLE OF NEUTROPHILS IN PARACETAMOL-INDUCED LIVER INJURY: Paracetamol-induced liver injury leads to the accumulation of neutrophils, which release lysosomal enzymes and generate superoxide anion radicals through the enzyme nicotinamide adenine dinucleotide phosphate oxidase. Hydrogen peroxide, which is influenced by the neutrophil-derived enzyme myeloperoxidase, generates hypochlorus acid as a potent oxidant. ROLE OF PEROXYNITRITE IN PARACETAMOL-INDUCED OXIDATIVE STRESS: Superoxide can react with nitric oxide to form peroxynitrite, as a potent oxidant. Nitrotyrosine is formed by the reaction of tyrosine with peroxynitrite in paracetamol hepatotoxicity. CONCLUSION: Overdose of paracetamol may produce severe liver injury with hepatocellular necrosis. The most important mechanisms of cell injury are metabolic activation of paracetamol, glutathione depletion, alkylation of proteins, especially mitochondrial proteins, and formation of reactive oxygen/nitrogen species. [PubMed Citation] [Order full text from Infotrieve]