The effect of diet on the toxicity of paracetamol and the safety of paracetamol-methionine mixtures

McLean, A. E. M.; Day, Pauline

doi:10.1016/0006-2952(75)90310-x

Cited by 155 publications

(46 citation statements)

References 15 publications

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“…Importantly for our study, furafylline had little effect on HRP enzyme activity up to 25 mM. Orally administered methionine or N-acetyl cysteine could also be administered to increase liver GSH levels (McLean and Day, 1975;Aebi and Lauterburg, 1992). This would decrease the susceptibility of the liver to damage by NAPQI by allowing increased amounts of mercapturic acid to be formed, as well as N-acetylcysteine conjugates.…”

Section: Discussionmentioning

confidence: 82%

Use of horseradish peroxidase for gene-directed enzyme prodrug therapy with paracetamol

2004

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Gene therapy is a potential method of treating cancer with a greater degree of targeting than conventional therapies. In addition, therapy can be directed towards cells within the tumour population that are traditionally resistant to current treatment schedules. Horseradish peroxidase (HRP) can oxidise paracetamol to N-acetyl-p-benzoquinoneimine via a one-electron pathway. Incubation of human cells expressing HRP with 0.5 -10 mM paracetamol reduced clonogenic survival, but had little effect on control cells. A small increase in apoptosis was seen and a decrease in the number of cells undergoing mitosis, consistent with reports in hepatocytes using higher paracetamol concentrations. The cytotoxicity was also seen under conditions of severe hypoxia (catalyst induced anoxia), indicating that the HRP/paracetamol combination may be suitable for hypoxia-targeted gene therapy.

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Section: Discussionmentioning

confidence: 82%

Use of horseradish peroxidase for gene-directed enzyme prodrug therapy with paracetamol

2004

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“…Oral administration of sufficient acetaminophen to produce plasma levels in the millimolar range would carry the danger of hepatotoxicity. However, it is possible to selectively protect the liver from any toxic effects of acetaminophen by oral administration of GSH precursors such as methionine or N-acetylcysteine 16 that elevate GSH in the liver but not in other tissues. 17 Activation of acetaminophen in the liver may also be reduced by inhibition of liver P450 activity before GDEPT; for example, the mechanistic noncompetitive inhibitor of human CYP1A2, furafylline, 18 could be administered before GDEPT to eliminate hepatic CYP1A2 activity for the duration of the treatment; after plasma furafylline is cleared, the CYP1A2 activity expressed in transfected tumor cells would be unaffected.…”

Section: Discussionmentioning

confidence: 99%

The potential of acetaminophen as a prodrug in gene-directed enzyme prodrug therapy

Thatcher¹,

Edwards²,

Lemoine

et al. 2000

Cancer Gene Ther

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Acetaminophen is oxidized by human CYP1A2 to the cytotoxic metabolite N-acetylbenzoquinoneimine (NABQI). Incubation of cells transfected with human CYP1A2 (H1A2 MZ cells) with 4 -20 mM acetaminophen for 6 hours at 37°C caused extensive cytotoxicity (cell viability Ͻ10%). In contrast, nontransfected V79 MZ cells were unaffected (viability Ͼ95%). By mixing H1A2 MZ cells with V79 MZ cells in various proportions and incubating with 4 mM acetaminophen, it was shown that the NABQI released from H1A2 MZ cells also caused cytotoxicity of bystander cells. Thus, in a mixture containing 5% H1A2 MZ cells, exposure to 4 mM acetaminophen for 6 hours resulted in complete cell killing by 24 hours. A similar bystander effect was found by incubating the same proportion of CYP1A2-containing cells with ovarian tumor-derived SK-OV-3 cells or colon tumor-derived HCT116 cells. However, breast tumor-derived MDA-MB-361 cells displayed resistance to the cytotoxic effect of NABQI, and it was necessary to increase the proportion of H1A2 MZ cells to 50% to achieve complete cell killing. In conclusion, the use of acetaminophen as prodrug and CYP1A2 as an activating enzyme is a promising combination for gene-directed enzyme prodrug therapy. Cancer Gene Therapy (2000) 7, 521-525

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“…The use of methionine (McLean and Day, 1975;Lancet, 1975) has already been shown to have some protective effect with respect to paracetamol toxicity, and it has been postulated that methionine and/or cysteamine (Mrochek et al, 1974) may supplement existing stocks of reduced thiols such as glutathione used within the hepatocyte to neutralise toxic paracetamol products which are produced by cytochrome P450 oxidase. We have no evidence to confirm or refute this theory.…”

Section: Side Effectsmentioning

confidence: 99%

“…It has been demonstrated in animals and man that methionine (McLean and Day, 1975;Mrochek et al, 1974) and cysteamine (Strubelt et al, 1974) may protect against paracetamol-induced liver damage. In this paper we compare the use of cysteamine and amino-acid solutions containing methionine and/or cysteine in acute paracetamol poisoning.…”

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confidence: 99%

Therapeutic Comparison of Thiol Compounds in Severe Paracetamol Poisoning

et al. 1977

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Twelve patients with toxic blood concentrations of paracetamol were treated with either cysteamine or amino-acid solution. None of the patients developed severe liver damage, although transient mild biochemical abnormalities developed in three. None of the patients treated with amino-acid solution had side effects due to therapy, whereas all those treated with cysteamine did. It is recommended that amino-acid solutions be used as a temporary measure in patients suspected of massive paracetamol overdose while awaiting estimation of blood paracetamol concentration.

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The effect of diet on the toxicity of paracetamol and the safety of paracetamol-methionine mixtures

Cited by 155 publications

References 15 publications

Use of horseradish peroxidase for gene-directed enzyme prodrug therapy with paracetamol

Use of horseradish peroxidase for gene-directed enzyme prodrug therapy with paracetamol

The potential of acetaminophen as a prodrug in gene-directed enzyme prodrug therapy

Therapeutic Comparison of Thiol Compounds in Severe Paracetamol Poisoning

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