Effects of ethanol ingestion on the metabolism of a hepatotoxic dose of paracetamol in mice

Jm, Tredger; Hm, Smith; Rb, Read; Williams, Roger

doi:10.3109/00498258609043556

Cited by 15 publications

(9 citation statements)

References 20 publications

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“…While chronic ethanol increases risk from acute paracetamol dosing (121,189,214) on the basis of induced P450 paracetamol metabolism, and consequent increased formation of NAPQI, or decreased glutathione supply or hepatic regeneration power (118), acute ethanol coadministration with paracetamol may be somewhat hepatoprotective (212,214) presumably by competitive inhibition of P450 paracetamol metabolism to NAPQI.…”

Section: Toxicologymentioning

confidence: 99%

Paracetamol: New Vistas of an Old Drug

et al. 2006

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Paracetamol (acetaminophen) is one of the most popular and widely used drugs for the treatment of pain and fever. It occupies a unique position among analgesic drugs. Unlike NSAIDs it is almost unanimously considered to have no antiinflammatory activity and does not produce gastrointestinal damage or untoward cardiorenal effects. Unlike opiates it is almost ineffective in intense pain and has no depressant effect on respiration. Although paracetamol has been used clinically for more than a century, its mode of action has been a mystery until about one year ago, when two independent groups (Zygmunt and colleagues and Bertolini and colleagues) produced experimental data unequivocally demonstrating that the analgesic effect of paracetamol is due to the indirect activation of cannabinoid CB 1 receptors. In brain and spinal cord, paracetamol, following deacetylation to its primary amine (p-aminophenol), is conjugated with arachidonic acid to form N-arachidonoylphenolamine, a compound already known (AM404) as an endogenous cannabinoid. The involved enzyme is fatty acid amide hydrolase. N-arachidonoylphenolamine is an agonist at TRPV1 receptors and an inhibitor of cellular anandamide uptake, which leads to increased levels of endogenous cannabinoids; moreover, it inhibits cyclooxygenases in the brain, albeit at concentrations that are probably not attainable with analgesic doses of paracetamol. CB 1 receptor antagonist, at a dose level that completely prevents the analgesic activity of a selective CB 1 receptor agonist, completely prevents the analgesic ac- 250CNS Drug Reviews Vol. 12, No. 3-4, pp. 250-275 © 2006 tivity of paracetamol. Thus, paracetamol acts as a pro-drug, the active one being a cannabinoid. These findings finally explain the mechanism of action of paracetamol and the peculiarity of its effects, including the behavioral ones. Curiously, just when the first CB 1 agonists are being introduced for pain treatment, it comes out that an indirect cannabinomimetic had been extensively used (and sometimes overused) for more than a century.

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Section: Toxicologymentioning

confidence: 99%

Paracetamol: New Vistas of an Old Drug

et al. 2006

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“…When a single dose of ethanol is given at or about the same time as paracetamol, it protects animals against hepatotoxicity even if they have been sensitized by previous chronic administration of alcohol [71, 78, 81, 85, 129–134] . This protective effect is associated with inhibition of the toxic metabolic activation of paracetamol both in vivo [79, 82, 134–136] and in vitro [136, 137]. Ethanol protects at concentrations as low as 2 m m [137] but once it has disappeared from the system, paracetamol metabolism reverts to the previous state.…”

Section: Acute Vs Chronic Ethanolmentioning

confidence: 99%

“…However, there have been some anomalous findings. Thus chronic ethanol did not always cause induction [76, 81, 82, 143], and hamsters treated with chronic ethanol and then withdrawn from it for 24 h were more resistant to the toxicity of paracetamol than control animals not exposed to ethanol [76]. Nevertheless, the potentiation of the hepatotoxicity of paracetamol by chronic ethanol intake in animals forms the mainstay of the belief that there is similar enhancement of toxicity in chronic alcoholics.…”

Section: Acute Vs Chronic Ethanolmentioning

confidence: 99%

Paracetamol, alcohol and the liver

Prescott

2000

Brit J Clinical Pharma

197

106

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It is claimed that chronic alcoholics are at increased risk of paracetamol (acetaminophen) hepatotoxicity not only following overdosage but also with its therapeutic use. Increased susceptibility is supposed to be due to induction of liver microsomal enzymes by ethanol with increased formation of the toxic metabolite of paracetamol. However, the clinical evidence in support of these claims is anecdotal and the same liver damage after overdosage occurs in patients who are not chronic alcoholics. Many alcoholic patients reported to have liver damage after taking paracetamol with`therapeutic intent' had clearly taken substantial overdoses. No proper clinical studies have been carried out to investigate the alleged paracetamol± alcohol interaction and acute liver damage has never been produced by therapeutic doses of paracetamol given as a challenge to a chronic alcoholic.The paracetamol±alcohol interaction is complex; acute and chronic ethanol have opposite effects. In animals, chronic ethanol causes induction of hepatic microsomal enzymes and increases paracetamol hepatotoxicity as expected (ethanol primarily induces CYP2E1 and this isoform is important in the oxidative metabolism of paracetamol). However, in man, chronic alcohol ingestion causes only modest (about twofold) and short-lived induction of CYP2E1, and there is no corresponding increase (as claimed) in the toxic metabolic activation of paracetamol. The paracetamol±ethanol interaction is not speci®c for any one isoform of cytochrome P450, and it seems that isoenzymes other than CYP2E1 are primarily responsible for the oxidative metabolism of paracetamol in man. Acute ethanol inhibits the microsomal oxidation of paracetamol both in animals and man. This protects against liver damage in animals and there is evidence that it also does so in man. The protective effect disappears when ethanol is eliminated and the relative timing of ethanol and paracetamol intake is critical.In many of the reports where it is alleged that paracetamol hepatotoxicity was enhanced in chronic alcoholics, the reverse should have been the case because alcohol was actually taken at the same time as the paracetamol. Chronic alcoholics are likely to be most vulnerable to the toxic effects of paracetamol during the ®rst few days of withdrawal but maximum therapeutic doses given at this time have no adverse effect on liver function tests. Although the possibility remains that chronic consumption of alcohol does increase the risk of paracetamol hepatotoxicity in man (perhaps by impairing glutathione synthesis), there is insuf®cient evidence to support the alleged major toxic interaction. It is astonishing that clinicians and others have unquestioningly accepted this supposed interaction in man for so long with such scant regard for scienti®c objectivity.

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“…When ethanol is administered in a single dose or when it is administered long term to experimental animals and continued as acetaminophen is administered, decreased acetaminophen toxicity and a decrease in the formation of NAPQI are observed. [25][26][27][28][29] In experimental studies in nonalcoholic human subjects, inhibition of NAPQI formation is observed when ethanol is ingested with acetaminophen, consistent with the studies in animals.30 Studies in rats, mice, and baboons show that if enough time is allowed between the last dose of ethanol and the administration of acetaminophen for ethanol to be eliminated, long-term administration of ethanol enhances the formation of NAPQI in vivo, and that microsomes prepared from animals receiving multiple-dose ethanol also show enhanced NAPQI formation. 26,31"4 Similarly, if ethanol is interrupted for at least 12 hours in alcoholic patients, acetaminophen toxicity, CYP2El activity, and formation of NAPQI are increased.…”

Section: Effects Of Single-and Multiple-dose Ethanol On Acetaminophenmentioning

confidence: 99%