acetaminophen hepatotoxicity


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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."

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."

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) Maurel M, Rosenbaum J
Closing the gap on drug-induced liver injury.
Hepatology. 2012 Aug;56(2):781-3.
Drug-induced liver injury (DILI) limits the development and application of many therapeutic compounds and presents major challenges to the pharmaceutical industry and clinical medicine. Acetaminophen-containing compounds are among the most frequently prescribed drugs and are also the most common cause of DILI. Here we describe a pharmacological strategy that targets gap junction communication to prevent amplification of fulminant hepatic failure and acetaminophen-induced hepatotoxicity. We demonstrate that connexin 32 (Cx32), a key hepatic gap junction protein, is an essential mediator of DILI by showing that mice deficient in Cx32 are protected against liver damage, acute inflammation and death caused by liver-toxic drugs. We identify a small-molecule inhibitor of Cx32 that protects against liver failure and death in wild-type mice when co-administered with known hepatotoxic drugs. These findings indicate that gap junction inhibition could provide a pharmaceutical strategy to limit DILI and improve drug safety. (HEPATOLOGY 2012;). [PubMed Citation] [Order full text from Infotrieve]

2) Fakurazi S, Sharifudin SA, Arulselvan P
<em>Moringa oleifera</em> Hydroethanolic Extracts Effectively Alleviate Acetaminophen-Induced Hepatotoxicity in Experimental Rats through Their Antioxidant Nature.
Molecules. 2012;17(7):8334-50.
The aim of the study was to investigate the in vitro antioxidant properties Moringa oleifera Lam. (MO) extracts and its curative role in acetaminophen (APAP)- induced toxic liver injury in rats caused by oxidative damage. The total phenolic content and antioxidant properties of hydroethanolic extracts of different MO edible parts were investigated by employing an established in vitro biological assay. In the antihepatotoxic study, either flowers or leaves extract (200 mg/kg or 400 mg/kg, i.p) were administered an hour after APAP administration, respectively. N-Acetylcysteine was used as the positive control against APAP-induced hepatotoxicity. The levels of liver markers such as alanine aminotransferase (ALT) and the levels of oxidative damage markers including malondialdehyde (MDA), 4-hydroxynonenal (4-HNE) protein adduct, reduced glutathione (GSH), superoxide dismutase (SOD) and catalase (CAT) were analysed and compared between experimental groups. Among MO edible parts the flower extracts contain the highest total phenolic content and antioxidant capacity, followed by leaves extract. The oxidative marker MDA, as well as 4-HNE protein adduct levels were elevated and GSH, SOD and CAT were significantly decreased in groups treated with hepatotoxin. The biochemical liver tissue oxidative markers measured in the rats treated with MO flowers and leaves hydroethanolic extracts showed a significant (p < 0.05) reduction in the severity of the liver damage. The results of this study strongly indicate the therapeutic properties of MO hydroethanolic extracts against acute liver injury and thereby scientifically support its traditional use. [PubMed Citation] [Order full text from Infotrieve]

3) Khawaja A, Shahab A, Hussain SA
Acetaminophen induced Steven Johnson syndrome-toxic epidermal necrolysis overlap.
J Pak Med Assoc. 2012 May;62(5):524-7.
Steven Johnson Syndrome and Toxic Epidermal Necrolysis are rare but severe form of hypersensitivity inflammatory reactions to multiple offending agents including drugs. Acetaminophen is extensively used due to its analgesic and anti-pyretic properties. It is rendered to be relatively safe, with hepatotoxicity considered to be the major adverse effect. However, very few cases of Steven Johnson Syndrome and Toxic Epidermal Necrolysis have been reported with acetaminophen usage in the past. We present the case of a 40 years old lady who developed an overlap of the two condition after taking several doses of acetaminophen for fever. She presented with widespread maculopapular rash, stinging in the eyes, oral mucosal ulcerations and high grade fever. She was successfully treated with corticosteroid therapy along with the supportive treatment. This case addresses the fact, that severe hypersensitivity reactions can occur with acetaminophen which can be potentially life threatening. [PubMed Citation] [Order full text from Infotrieve]

4) Betto MR, Lazarotto LF, Watanabe TT, Driemeier D, Leite CE, Campos MM
Effects of treatment with enalapril on hepatotoxicity induced by acetaminophen in mice.
Naunyn Schmiedebergs Arch Pharmacol. 2012 Jul 3;
There is a current need for new therapeutic options for acetaminophen (APAP)-induced hepatotoxicity. Herein, we assessed the effects of prophylactic and therapeutic treatment with the angiotensin-converting enzyme (ACE) inhibitor, enalapril, on APAP-caused hepatotoxicity. Male and female C57BL/6 J mice were used, and hepatotoxicity was induced by a single application of APAP (400 mg/kg, i.p.). Macroscopic and histological liver alterations, serum alanine transaminase (ALT) and aspartate transaminase (AST) activity, liver catalase activity (CAT), reduced glutathione concentrations (GSH), hepatic measurement of neutrophil migration (myeloperoxidase, MPO activity), and caspase-3 liver expression were evaluated. The prophylactic and the therapeutic treatments with enalapril were able to markedly reduce the macroscopic and histological liver alterations as well as the caspase-3 immunopositivity. Both schedules of treatment were also effective in reducing GSH concentrations as well as neutrophil migration. Conversely, only the pre-treatment (but not the post-administration) with enalapril significantly reversed APAP-induced CAT decrease. Furthermore, the pre- or the post-treatment with enalapril largely reduced ALT and AST serum activity in APAP-intoxicated mice. The hepatoprotective effects of enalapril were comparable to those obtained with the clinically used compound N-acetylcysteine (NAC) when given in a therapeutic regimen. Data obtained with the prophylactic protocol of treatment might indicate that individuals under treatment with ACE inhibitors are less susceptible to the toxic effects of APAP. Additionally, the therapeutic approach allows us to suggest that enalapril might represent an innovative tool for treating APAP intoxication. [PubMed Citation] [Order full text from Infotrieve]

5) Moling O, Tappeiner L, Piccin A, Pagani E, Rossi P, Rimenti G, Vedovelli C, Mian P
Treatment of DIHS/DRESS syndrome with combined N-acetylcysteine, prednisone and valganciclovir - a hypothesis.
Med Sci Monit. 2012 Jun 28;18(7):CS57-62.
Background: Drug-induced hypersensitivity syndrome/drug reaction with eosinophilia and systemic symptoms (DIHS/DRESS) is a rare and severe adverse drug reaction with an associated mortality of 10-20%. Clinical worsening despite discontinuation of the culprit drug is considered a characteristic feature of DIHS/DRESS. Besides the early recognition of the syndrome and discontinuation of its causative drug, the mainstay of treatment is systemic corticosteroids. Nevertheless, treatment of severe DIHS/DRESS is not well defined, as corticosteroids may sometimes not be effective, and decreasing the dose may be associated with flaring of the disease.
Case Report: A 38-year-old woman with high fever, malaise, abdominal pain, rash, and elevated liver enzymes received immediate high-dose N-acetylcysteine, because acetaminophen hepatotoxicity was suspected. N-acetylcysteine administration was associated with a significant clinical improvement. However, within the next week DIHS/DRESS syndrome was diagnosed, which explained all the symptoms, and which was subsequently treated with prednisone and valganciclovir.
Conclusions: New options necessary to improve treatment of severe DIHD/DRESS have to consider its sequential pathogenetic mechanisms. N-acetylcysteine might neutralize the drug-derived reactive metabolites, which are responsible for protein adduct formation and specific T cell stimulation, and replete the glutathione stores that counterbalance oxidative stress. Prednisone might inhibit lymphoproliferation and valganciclovir might prevent complications related to HHV-6 reactivation. We therefore propose the unprecedented combination of N-acetylcysteine, prednisone and valganciclovir as a treatment option for DIHS/DRESS.
[PubMed Citation] [Order full text from Infotrieve]

6) He CY, Liang BB, Fan XY, Cao L, Chen R, Guo YJ, Zhao J
The dual role of osteopontin in acetaminophen hepatotoxicity.
Acta Pharmacol Sin. 2012 Jun 25;
Aim:Osteopontin (OPN), a multifunctional protein, has been reported to be protoxicant in acetaminophen hepatotoxicity. In this study, the mechanisms underlying the detrimental role of OPN in acetaminophen toxicity were explored.Methods:Male C57BL/6 (wild-type, WT) and OPN(-/-) mice were administered with acetaminophen (500 mg/kg, ip). After the treatment, serum transaminase (ALT), as well as OPN expression, histology changes, oxidative stress and inflammation response in liver tissue were studied. Freshly isolated hepatocytes of WT and OPN(-/-) mice were prepared.Results:Acetaminophen administration significantly increased OPN protein level in livers of WT mice. OPN expression was mainly localized in hepatic macrophages 6 h after the administration. In OPN(-/-) mice, acetaminophen-induced serum ALT release was reduced, but the centrilobular hepatic necrosis was increased. In OPN(-/-) mice, the expression of CYP2E1 and CYP1A2 in livers was significantly increased; GSH depletion and lipid peroxidation in livers were enhanced. On the other hand, OPN(-/-) mice exhibited less macrophage and neutrophil infiltration and reduced expression of proinflammatory cytokines TNF-? and IL-1? in livers. An anti-OPN neutralizing antibody significantly reduced acetaminophen-induced serum ALT level and inflammatory infiltration in livers of WT mice.Conclusion:OPN plays a dual role in acetaminophen toxicity: OPN in hepatocytes inhibits acetaminophen metabolism, while OPN in macrophages enhances acetaminophen toxicity via recruitment of inflammatory cells and production of proinflammatory cytokines. [PubMed Citation] [Order full text from Infotrieve]

7) He M, Zhang S, Jiao Y, Lin X, Huang J, Chen C, Chen Z, Huang R
Effects and mechanisms of rifampin on hepatotoxicity of acetaminophen in mice.
Food Chem Toxicol. 2012 Jun 19;50(9):3142-3149.
This study examined the effects and possible mechanisms of rifampin against acetaminophen-induced hepatotoxicity in mice. Rifampin significantly enhanced the biotransformation of acetaminophen, evidenced by the increase in p-aminophenol formation in rifampin-treated microsomes and the increase in plasma clearance rate of acetaminophen. Pretreatment with rifampin significantly decreased serum alanine transaminase (ALT) activities, aspartate transaminase (AST) activities and prevented severe liver necrosis following acetaminophen overdose. The contents and activities of microsomal drug-metabolizing enzyme were less affected in rifampin-pretreated mice in comparison to the animals treated with acetaminophen alone. Rifampin was capable of increasing glutathione (GSH) level and GSH reductase activity and reducing GSH depletion and the decrease in GSH reductase activity by acetaminophen in mice. In addition, it was found that the microsomal Ca(2+)-ATPase activity was not directly related to acetaminophen toxic species generated in the P450 enzyme system in vitro. These findings suggest that rifampin has species-specific effects on the liver against acetaminophen-induced hepatotoxicity in mice, which increase the level of GSH by promoting GSH regeneration. [PubMed Citation] [Order full text from Infotrieve]

8) Saiman Y, Friedman SL
The role of chemokines in acute liver injury.
Front Physiol. 2012;3:213.
Chemokines are small molecular weight proteins primarily known to drive migration of immune cell populations. In both acute and chronic liver injury, hepatic chemokine expression is induced resulting in inflammatory cell infiltration, angiogenesis, and cell activation and survival. During acute injury, massive parenchymal cell death due to apoptosis and/or necrosis leads to chemokine production by hepatocytes, cholangiocytes, Kupffer cells, hepatic stellate cells, and sinusoidal endothelial cells. The specific chemokine profile expressed during injury is dependent on both the type and course of injury. Hepatotoxicity by acetaminophen for example leads to cellular necrosis and activation of Toll-like receptors while the inciting insult in ischemia reperfusion injury produces reactive oxygen species and subsequent production of pro-inflammatory chemokines. Chemokine expression by these cells generates a chemoattractant gradient promoting infiltration by monocytes/macrophages, NK cells, NKT cells, neutrophils, B cells, and T cells whose activity are highly regulated by the specific chemokine profiles within the liver. Additionally, resident hepatic cells express chemokine receptors both in the normal and injured liver. While the role of these receptors in normal liver has not been well described, during injury, receptor up-regulation, and chemokine engagement leads to cellular survival, proliferation, apoptosis, fibrogenesis, and expression of additional chemokines and growth factors. Hepatic-derived chemokines can therefore function in both paracrine and autocrine fashions further expanding their role in liver disease. More recently it has been appreciated that chemokines can have diverging effects depending on their temporal expression pattern and the type of injury. A better understanding of chemokine/chemokine receptor axes will therefore pave the way for development of novel targeted therapies for the treatment of liver disease. [PubMed Citation] [Order full text from Infotrieve]

9) Ward J, Bala S, Petrasek J, Szabo G
Plasma microRNA profiles distinguish lethal injury in acetaminophen toxicity: A research study.
World J Gastroenterol. 2012 Jun 14;18(22):2798-804.
[PubMed Citation] [Order full text from Infotrieve]

10) Madhavan V, Pandey AS, Murali A, Yoganarasimhan SN
Protective Effects of Capparis sepiaria Root Extracts against Acetaminophen-Induced Hepatotoxicity in Wistar Rats.
J Complement Integr Med. 2012;9(1):1-12.
Capparis sepiaria L. known as Himsra is an important drug in Ayurveda. In this study extracts of the root of C. sepiaria were evaluated for their hepatoprotective potential on acetaminophen-induced hepatotoxicity in albino Wistar rats. The extent of hepatoprotection was evaluated by estimating the serum levels of hepatic transaminases (SGPT and SGOT), alkaline phosphatase (ALP), total protein (TP), and bilirubin (total and direct). Aqueous and ethanol extracts of C. sepiaria significantly reduced the increased liver weight as well as serum levels of SGPT, SGOT, ALP, and bilirubin, and normalized the reduced serum protein levels in the treated rats. These observations were supported by the results of histopathology studies as well. The extracts were also subjected to preliminary organic analysis and chromatographic studies including HPTLC finger print studies. The results indicate that the roots of C. sepiaria show significant hepatoprotective effect on acetaminophen-induced hepatotoxicity, thus substantiating its use as a potential hepatoprotective drug. [PubMed Citation] [Order full text from Infotrieve]

11) Clark R, Fisher JE, Sketris IS, Johnston GM
Population prevalence of high dose paracetamol in dispensed paracetamol/opioid prescription combinations: an observational study.
BMC Clin Pharmacol. 2012 Jun 18;12(1):11.
ABSTRACT: BACKGROUND: Paracetamol (acetaminophen) is generally considered a safe medication, but is associated with hepatotoxicity at doses above doses of 4.0 g/day, and even below this daily dose in certain populations. METHODS: The Nova Scotia Prescription Monitoring Program (NSPMP) in the Canadian province of Nova Scotia is a legislated organization that collects dispensing information on all out-of-hospital prescription controlled drugs dispensed for all Nova Scotia residents. The NSPMP provided data to track all paracetamol/opioids redeemed by adults in Nova Scotia, from July 1, 2005 to June 30, 2010. Trends in the number of adults dispensed these prescriptions and the numbers of prescriptions and tablets dispensed over this period were determined. The numbers and proportions of adults who filled prescriptions exceeding 4.0g/day and 3.25g/day were determined for the one-year period July 1, 2009 to June 30, 2010. Data were stratified by sex and age (<65 versus 65+). RESULTS: Both the number of prescriptions filled and the number of tablets dispensed increased over the study period, although the proportion of the adult population who filled at least one paracetamol/opioid prescription was lower in each successive one-year period. From July 2009 to June 2010, one in 12 adults (n=59,197) filled prescriptions for over 13 million paracetamol/opioid tablets. Six percent (n=3,786) filled prescriptions that exceeded 4.0 g/day and 18% (n=11,008) exceeded 3.25 g/day at least once. These findings exclude non-prescription paracetamol and paracetamol-only prescribed medications. CONCLUSIONS: A substantial number of individuals who redeem prescriptions for paracetamol/opioid combinations may be at risk of paracetamol-related hepatotoxicity. Healthcare professionals must be vigilant when prescribing and dispensing these medications in order to reduce the associated risks. [PubMed Citation] [Order full text from Infotrieve]

12) Jaeschke H, McGill MR, Williams CD
The pathophysiological relevance of neutrophils in acetaminophen hepatotoxicity.
Hepatology. 2012 Jun 18;
[PubMed Citation] [Order full text from Infotrieve]

13) Arakawa S, Maejima T, Fujimoto K, Yamaguchi T, Yagi M, Sugiura T, Atsumi R, Yamazoe Y
Resistance to acetaminophen-induced hepatotoxicity in <i>glutathione S-transferase Mu 1</i>-null mice.
J Toxicol Sci. 2012;37(3):595-605.
We investigated the role of glutathione S-transferases Mu 1 (GSTM1) in acetaminophen (APAP)-induced hepatotoxicity using Gstm1-null mice. A single oral administration of APAP resulted in a marked increase in plasma alanine aminotransferase accompanied by hepatocyte necrosis 24 hr after administration in wild-type mice, but its magnitude was unexpectedly attenuated in Gstm1-null mice. Therefore, it is suggested that Gstm1-null mice are resistant to APAP-induced hepatotoxicity. To examine the mechanism of this resistance in Gstm1-null mice, we measured phosphorylation of c-jun N-terminal kinase (JNK), which mediates the signal of APAP-induced hepatocyte necrosis, by Western blot analysis 2 and 6 hr after APAP administration. A marked increase in phosphorylated JNK was observed in wild-type mice, but the increase was markedly suppressed in Gstm1-null mice. Therefore, it is suggested that suppressed phosphorylation of JNK may be a main mechanism of the resistance to APAP-induced hepatotoxicity in Gstm1-null mice, although other possibilities of the mechanism cannot be eliminated. Additionally, phosphorylation of glycogen synthase kinase-3? and mitogen-activated protein kinase kinase 4, which are upstream kinases of JNK in APAP-induced hepatotoxicity, were also suppressed in Gstm1-null mice. A decrease in liver total glutathione 2 hr after APAP administration, which is an indicator for exposure to N-acetyl-p-benzoquinoneimine, the reactive metabolite of APAP, were similar in wild-type and Gstm1-null mice. In conclusion, Gstm1-null mice are considered to be resistant to APAP-induced hepatotoxicity perhaps by the suppression of JNK phosphorylation. This study indicates the novel role of GSTM1 as a factor mediating the cellular signal for APAP-induced hepatotoxicity. [PubMed Citation] [Order full text from Infotrieve]

14) Michael Brown J, Ball JG, Wright MS, Van Meter S, Valentovic MA
Novel protective mechanisms for S-adenosyl-l-methionine against acetaminophen hepatotoxicity: Improvement of key antioxidant enzymatic function.
Toxicol Lett. 2012 Aug 3;212(3):320-8.
Acetaminophen (APAP) overdose leads to severe hepatotoxicity, increased oxidative stress and mitochondrial dysfunction. S-adenosyl-l-methionine (SAMe) protects against APAP toxicity at a mmol/kg equivalent dose to N-acetylcysteine (NAC). SAMe acts as a principle biological methyl donor and participates in polyamine synthesis which increase cell growth and has a role in mitochondrial protection. The purpose of the current study tested the hypothesis that SAMe protects against APAP toxicity by maintaining critical antioxidant enzymes and markers of oxidative stress. Male C57Bl/6 mice were treated with vehicle (Veh; water 15ml/kg, ip), SAMe (1.25mmol/kg, ip), APAP (250mg/kg, ip), and SAMe+APAP (SAMe given 1h following APAP). Liver was collected 2 and 4h following APAP administration; mitochondrial swelling as well as hepatic catalase, glutathione peroxidase (GPx), glutathione reductase, and both Mn- and Cu/Zn-superoxide dismutase (SOD) enzyme activity were evaluated. Mitochondrial protein carbonyl, 3-nitrotyrosine cytochrome c leakage were analyzed by Western blot. SAMe significantly increased SOD, GPx, and glutathione reductase activity at 4h following APAP overdose. SAMe greatly reduced markers of oxidative stress and cytochrome C leakage following APAP overdose. Our studies also demonstrate that a 1.25mmol/kg dose of SAMe does not inhibit CYP 2E1 enzyme activity. The current study identifies a plausible mechanism for the decreased oxidative stress observed when SAMe is given following APAP. [PubMed Citation] [Order full text from Infotrieve]

15) Aubert J, Begriche K, Delannoy M, Morel I, Pajaud J, Ribault C, Lepage S, McGill MR, Lucas-Clerc C, Turlin B, Robin MA, Jaeschke H, Fromenty B
Differences in early acetaminophen hepatotoxicity between obese ob/ob and db/db mice.
J Pharmacol Exp Ther. 2012 May 30;
Clinical investigations suggest that hepatotoxicity after acetaminophen (APAP) overdose could be more severe in the context of obesity and nonalcoholic fatty liver disease. The pre-existence of fat accumulation and cytochrome P450 2E1 (CYP2E1) induction could be major mechanisms accounting for such hepatic susceptibility. To explore this issue, experiments were performed in obese and diabetic ob/ob and db/db mice. Preliminary investigations performed in male and female wild-type, ob/ob and db/db mice showed a selective increase in hepatic CYP2E1 activity in female db/db mice. However, liver triglycerides in these animals were significantly lower compared to ob/ob mice. Next, APAP (500 mg/kg) was administered in female wild-type, ob/ob and db/db mice and investigations were carried out 0.5, 2, 4 and 8 h after APAP intoxication. Liver injury 8 h after APAP intoxication was higher in db/db mice, as assessed by plasma transaminases, liver histology and TUNEL assay. In db/db mice, however, the extent of hepatic glutathione depletion, levels of APAP-protein adducts, c-jun N-terminal kinase (JNK) activation, changes in gene expression and mitochondrial DNA levels were not greater compared to the other genotypes. Furthermore, in the db/db genotype, plasma lactate and ?-hydroxybutyrate were not specifically altered, whereas plasma levels of APAP-glucuronide were intermediary between wild-type and ob/ob mice. Thus, early APAP-induced hepatotoxicity was greater in db/db than in ob/ob mice, despite less severe fatty liver and similar basal levels of transaminases. Hepatic CYP2E1 induction could have an important pathogenic role when APAP-induced liver injury occurs in the context of obesity and related metabolic disorders. [PubMed Citation] [Order full text from Infotrieve]

16) Jin SM, Park K
Acetaminophen induced cytotoxicity and altered gene expression in cultured cardiomyocytes of h(9)c(2) cells.
Environ Health Toxicol. 2012;27:e2012011.
[PubMed Citation] [Order full text from Infotrieve]

17) Wancket LM, Meng X, Rogers LK, Liu Y
Mitogen-activated Protein Kinase Phosphatase (Mkp)-1 Protects Mice against Acetaminophen-induced Hepatic Injury.
Toxicol Pathol. 2012 May 23;
c-Jun N-terminal kinase (JNK) activation promotes hepatocyte death during acetaminophen overdose, a common cause of drug-induced liver failure. While mitogen-activated protein kinase (MAPK) phosphatase (Mkp)-1 is a critical negative regulator of JNK MAPK, little is known about the role of Mkp-1 during hepatotoxicity. In this study, we evaluated the role of Mkp-1 during acute acetaminophen toxicity. Mkp-1(+/+) and Mkp-1(-/-) mice were dosed ip with vehicle or acetaminophen at 300 mg/kg (for mechanistic studies) or 400 mg/kg (for survival studies). Tissues were collected 1-6 hr post 300 mg/kg dosing to assess glutathione levels, organ damage, and MAPK activation. Mkp-1(-/-) mice exhibited more rapid plasma clearance of acetaminophen than did Mkp-1(+/+) mice, indicated by a quicker decline of plasma acetaminophen level. Moreover, Mkp-1(-/-) mice suffered more severe liver injury, indicated by higher plasma alanine transaminase activity and more extensive centrilobular apoptosis and necrosis. Hepatic JNK activity in Mkp-1(-/-) mice was higher than in Mkp-1(+/+) mice. Finally, Mkp-1(-/-) mice displayed a lower overall survival rate and shorter median survival time after dosing with 400 mg/kg acetaminophen. The more severe phenotype exhibited by Mkp-1(-/-) mice indicates that Mkp-1 plays a protective role during acute acetaminophen overdose, potentially through regulation of JNK. [PubMed Citation] [Order full text from Infotrieve]

18) Liu WX, Jia FL, He YY, Zhang BX
Protective effects of 5-methoxypsoralen against acetaminophen-induced hepatotoxicity in mice.
World J Gastroenterol. 2012 May 14;18(18):2197-202.
[PubMed Citation] [Order full text from Infotrieve]

19) van Swelm R, Laarakkers C, Blous L, Peters J, Blaney Davidson E, van der Kraan P, Swinkels D, Masereeuw R, Russel F
Acute acetaminophen intoxication leads to hepatic iron loading by decreased hepcidin synthesis.
Toxicol Sci. 2012 May 18;
Acetaminophen (APAP), a major cause of acute liver injury in the western world, is mediated by metabolism and oxidative stress. Recent studies have suggested a role for iron in potentiating APAP-induced liver injury, although its regulatory mechanism is not completely understood. The current study was designed to unravel the iron-regulating pathways in mice after APAP-induced hepatotoxicity. Mice with severe injury showed a significant increase in liver iron concentration and oxidative stress. Concurrently, the plasma concentration of hepcidin, the key regulator in iron metabolism, and hepatic hepcidin antimicrobial peptide (Hamp) mRNA expression levels were significantly reduced. We showed that hepcidin transcription was inhibited via several hepcidin-regulating factors, including the bone morphogenetic protein / small mother against decapentaplegic (BMP/SMAD) pathway, CCAAT/enhancer-binding protein ? (C/EBP?) and possibly also via erythropoietin (EPO). Down-regulation of the BMP/SMAD signaling pathway was most likely caused by hypoxia-inducible factor 1? (HIF-1?), which was increased in mice with severe APAP-induced liver injury. HIF-1? stimulates cleaving of hemojuvelin, the cofactor of the BMP receptor, thereby blocking BMP-induced signaling. In addition, gene expression levels of C/ebp? were significantly reduced and Epo mRNA expression levels were significantly increased after APAP intoxication. These factors are regulated through HIF-1? during oxidative stress and suggest that HIF-1? is a key modulator in reduced hepcidin transcription after APAP-induced hepatotoxicity. In conclusion, acute APAP-induced liver injury leads to activation of HIF-1? which results in a down-regulation in hepcidin expression through a BMP/SMAD signaling pathway and through C/EBP? inhibition. Eventually, this leads to hepatic iron loading associated with APAP cytotoxicity. [PubMed Citation] [Order full text from Infotrieve]

20) Yamashina S
Reply to the letter "Autophagy and acetaminophen hepatotoxicity: how useful are Atg7-deficient mice?".
J Gastroenterol. 2012 Jul;47(7):847-8.
[PubMed Citation] [Order full text from Infotrieve]