Potentiation of the Toxic Effects of Acetaminophen in Mice by Concurrent Infection with Influenza B Virus: a Possible Mechanism for Human Reye's Syndrome?

MacDonald, M G; McGrath, Philip P.; McMartin, Donald N.; Washington, George; Hudák, Gabriella

doi:10.1203/00006450-198402000-00014

Cited by 18 publications

(8 citation statements)

References 9 publications

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“…As with ethanol, this enhanced hepatotoxicity has been suggested to be due to activation of certain components of the cytochrome P450 system by the viral infection. However, the experimental results in mice [103] did not support this hypothesis.…”

Section: Infectious Diseases and Paracetamol-induced Hepatotoxicitymentioning

confidence: 85%

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A review of the hepatotoxicity of paracetamol at therapeutic or near‐therapeutic dose levels, with particular reference to alcohol abusers

Collins

Starmer

1995

Drug and Alcohol Review

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The number of published reports associating hepatotoxicity with paracetamol ingestion at therapeutic or near-therapeutic dose levels is small but is, nevertheless, suggestive of a relationship. There is however, mounting evidence that certain groups of patients, such as alcohol-dependent people, patients receiving enzyme-inducing drugs (particularly anti-convulsant and anti-tuberculosis medications) as well as those with certain infectious diseases, are rendered more susceptible to paracetamol-induced hepatotoxicity. Seventy-four case reports where therapeutic or near-therapeutic doses of paracetamol resulted in hepatic injury are reviewed and factors and mechanisms which might explain this apparently increased vulnerability to damage are discussed.

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Section: Infectious Diseases and Paracetamol-induced Hepatotoxicitymentioning

confidence: 85%

“…Potentiation of paracetamol-induced hepatotoxicity has been shown [103] in mice which were pre-infected with influenza B vires. As with ethanol, this enhanced hepatotoxicity has been suggested to be due to activation of certain components of the cytochrome P450 system by the viral infection.…”

Section: Infectious Diseases and Paracetamol-induced Hepatotoxicitymentioning

confidence: 99%

A review of the hepatotoxicity of paracetamol at therapeutic or near‐therapeutic dose levels, with particular reference to alcohol abusers

Collins

Starmer

1995

Drug and Alcohol Review

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“…The hepatotoxicity of several drugs is increased by mild viral infections,1–13 which may cause subliminal stimulation of death receptors 14–18. Because drug‐induced toxicity is often due to the formation of reactive metabolites,19 we tested the hypothesis that subliminal death receptor stimulation may increase metabolite‐mediated hepatotoxicity.…”

Section: Discussionmentioning

confidence: 99%

“…Not all drugs whose hepatotoxicity is increased by viral infections1–13 are transformed into reactive metabolites. APAP,21 isoniazid45 and buprenorphine46 form reactive metabolites (and azathioprine depletes GSH),47 but aspirin, ibuprofen, and nucleoside reverse transcriptase inhibitors are mostly toxic through their mitochondrial effects 48.…”

Section: Discussionmentioning

confidence: 99%

“…Although lethal overdoses of aspirin cause microvesicular steatosis in children, therapeutic doses do not, unless aspirin is administered during viral infections 9. Finally, the hepatotoxicity of acetaminophen—also called paracetamol or N ‐acetyl‐ p ‐aminophenol (APAP)—may be increased in patients with infectious mononucleosis,10 measles,11 or acute hepatitis A or B,12 as well as in mice with influenza B virus infection 13…”

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Subliminal Fas stimulation increases the hepatotoxicity of acetaminophen and bromobenzene in mice

et al. 2004

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The hepatotoxicity of several drugs is increased by mild viral infections. During such infections, death receptor ligands are expressed at low levels, and most parenchymal cells survive. We tested the hypothesis that subliminal death receptor stimulation may aggravate the hepatotoxicity of drugs, which are transformed by cytochrome P-450 cytochrome P-450 into glutathione-depleting reactive metabolites. Twenty-four-hour-fasted mice were pretreated with a subtoxic dose of the agonistic Jo2 anti-Fas antibody (1 g per mouse) 3 hours before acetaminophen (500 mg/kg) or 1 hour before bromobenzene (400 mg/kg) administration. Administration of Jo2 alone increased hepatic inducible nitric oxide synthase nitric oxide synthase but did not modify serum alanine aminotransferase (ALT), hepatic adenosine triphosphate (ATP), glutathione (GSH), cytochrome P-450, cytosolic cytochrome c, caspase-3 activity or hepatic morphology. However, pretreating mice with Jo2 further decreased both hepatic GSH and ATP by 40% 4 hours after acetaminophen administration, and further increased serum ALT and the area of centrilobular necrosis at 24 hours. In mice pretreated with the Jo2 antibody before bromobenzene administration, hepatic GSH 4 hours after bromobenzene administration was 51% lower than in mice treated with bromobenzene alone, and serum ALT activity at 24 hours was 47-fold higher. In conclusion, administration of a subtoxic dose of an agonistic anti-Fas antibody before acetaminophen or bromobenzene increases metabolite-mediated GSH depletion and hepatotoxicity. Subliminal death receptor stimulation may be one mechanism whereby mild viral infections can increase druginduced toxicity. (HEPATOLOGY 2004;39:655-666.)

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Hepatitis during measles in young adults: Possible role of antipyretic drugs

Ackerman¹,

Flugelman²,

Wax³

et al. 1989

Hepatology

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Fifty-six per cent of 118 young adults observed during a recent measles epidemic had some disturbance on liver function tests. Five per cent developed overt jaundice. Patients treated for fever with paracetamol were found to have significantly higher rates of transaminase impairment compared to those treated with dipyrone. Sixty-five and 58% of patients given paracetamol had elevated ALT and AST levels, respectively. Only 15% of patients given dipyrone had elevated levels of these two enzymes (p less than 0.01 for ALT and p less than 0.02 for AST). The mean levels of transaminases and bilirubin in the paracetamol-treated patients were significantly higher than those found in the dipyrone-treated patients [92 +/- 86 vs. 42 +/- 49 IU (p less than 0.02) for AST and 12 +/- 6.0 vs. 7.0 +/- 2.0 mumoles per liter (p less than 0.01) for bilirubin]. The cumulative dose of paracetamol in those who had impaired liver function was higher than that ingested by patients who did not develop liver damage, although still within the usual therapeutic range [11.6 +/- 5.8 vs. 7.6 +/- 4.2 gm (p = 0.02)]. The possible ways in which measles infection and paracetamol in combination can lead to hepatic damage are discussed.

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Potentiation of the Toxic Effects of Acetaminophen in Mice by Concurrent Infection with Influenza B Virus: a Possible Mechanism for Human Reye's Syndrome?

Cited by 18 publications

References 9 publications

A review of the hepatotoxicity of paracetamol at therapeutic or near‐therapeutic dose levels, with particular reference to alcohol abusers

A review of the hepatotoxicity of paracetamol at therapeutic or near‐therapeutic dose levels, with particular reference to alcohol abusers

Subliminal Fas stimulation increases the hepatotoxicity of acetaminophen and bromobenzene in mice

Hepatitis during measles in young adults: Possible role of antipyretic drugs

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