N-Hydroxyphenacetin as a precursor of 3-subst1tuted 4-hydroxyacetanilide metabolites of phenacetin

Calder, I. C.; Creek, M.J.; Williams, PJ

doi:10.1016/0009-2797(74)90054-4

Cited by 33 publications

(4 citation statements)

References 8 publications

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“…The possibility that NAPQI reacts with other nucleophilic residues has received comparatively little attention. There are scattered reports in the literature that suggest that the amino acid side chains of methionine, lysine, and tyrosine might form covalent adducts with NAPQI, but these adducts have not been isolated and structurally characterized using techniques such as high resolution mass spectrometry (HRMS), MS/MS, and 1 H nuclear magnetic resonance (NMR) spectroscopy. Here, we (i) examine the reaction of NAPQI with N -acetyl methyl ester derivatives of selected amino acids NHAc-X-OMe (where X = Cys, Tyr, Trp, His, Lys, Arg, Met, Gln, Glu, Thr, and Ala) by isolating covalent adducts using preparative high performance liquid chromatography (HPLC) followed by identification with MS and NMR methods; (ii) use HPLC coupled with HRMS and MS/MS techniques to examine the related adducts formed in the reaction of NAPQI with the peptides GAIL-X-GAILR (where X = Cys, Met, Tyr, or Trp); and (iii) identify the adducts formed upon APAP incubation with the peptides GAIL-X-GAILR in rat liver microsomes.…”

Section: Introductionmentioning

confidence: 99%

What Are the Potential Sites of Protein Arylation by N-Acetyl-p-benzoquinone Imine (NAPQI)?

Leeming

Gamon

Wille

et al. 2015

Chem. Res. Toxicol.

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Acetaminophen (paracetamol, APAP) is a safe and widely used analgesic medication when taken at therapeutic doses. However, APAP can cause potentially fatal hepatotoxicity when taken in overdose or in patients with metabolic irregularities. The production of the electrophilic and putatively toxic compound N-acetyl-p-benzoquinone imine (NAPQI), which cannot be efficiently detoxicated at high doses, is implicated in APAP toxicity. Numerous studies have identified that excess NAPQI can form covalent linkages to the thiol side chains of cysteine residues in proteins; however, the reactivity of NAPQI toward other amino acid side chains is largely unexplored. Here, we report a survey of the reactivity of NAPQI toward 11 N-acetyl amino acid methyl esters and four peptides. (1)H NMR analysis reveals that NAPQI forms covalent bonds to the side-chain functional groups of cysteine, methionine, tyrosine, and tryptophan residues. Analogous reaction products were observed when NAPQI was reacted with synthetic model peptides GAIL-X-GAILR for X = Cys, Met, Tyr, and Trp. Tandem mass spectrometry peptide sequencing showed that the NAPQI modification sites are located on the "X" residue in each case. However, when APAP and the GAIL-X-GAILR peptide were incubated with rat liver microsomes that contain many metabolic enzymes, NAPQI formed by oxidative metabolism reacted with GAIL-C-GAILR exclusively. For the peptides where X = Met, Tyr, and Trp, competing reactions between NAPQI and alternative nucleophiles precluded arylation of the target peptide by NAPQI. Although Cys residues are favorably targeted under these conditions, these data suggest that NAPQI can, in principle, also damage proteins at Met, Tyr, and Trp residues.

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Section: Introductionmentioning

confidence: 99%

What Are the Potential Sites of Protein Arylation by N-Acetyl-p-benzoquinone Imine (NAPQI)?

Leeming

Gamon

Wille

et al. 2015

Chem. Res. Toxicol.

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“…More recently it was found that N-acetoxyphenacetin reacted with methionine probably through the N-acetyl-p-benzoquinoneimine to yield 3MT-4HA. 3 Our studies indicating that both phenacetin and acetaminophen undergo metabolism to 3MT -4HA in conjunction with the above studies 3 suggest that N-hydroxylation of phenacetin or acetaminophen or both followed by esterification of the hydroxyl group may be the pathway responsible for the formation of 3MT-4HA. Evidence for the metabolic N-hydroxylation ofphenacetin 6 and acetaminophen lO was recently provided.…”

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confidence: 59%

Formation of a thiomethyl metabolite of phenacetin and acetaminophen in dogs and man

Klutch

Levin

Chang

et al. 1978

Clin Pharma and Therapeutics

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Conjugates of 3-methylthio-4-hydroxyactanilide were found in the urine of dogs and humans treated with phenacetin (4-ethoxyacetanilide) or acetaminophen (4-hydroxyacetanilide). About 1% to 3% of the administered dose was excreted as this thiomethyl metabolite after administration of phenacetin or acetaminophen to dogs. An average of 0.39% of the dose was excreted in the urine as 3-methylthio-4-hydroxyacetanilide conjugates after administration of phenacetin to several subjects, and an average of 0.66% of the dose was excreted as this metabolite in the urine after administration of acetaminophen to humans. The possibility that the thiomethyl metabolite is derived from a mercapturic acid conjugate or an N-hydroxy derivative of phenacetin or acetaminophen is discussed.

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“…This mechanism was subsequently modified following reports by Dr. Ian Calder's laboratory in Australia that N-acetyl-p-benzoquinone imine (NAPQI) was an electrophilic species (Calder et al 1973;Calder et al 1974;Calder et al 1981). They were able to synthesize it by oxidation with lead tetra-acetate, but it rapidly decomposed.…”

Section: Studies On the Mechanism Of Metabolic Activationmentioning

confidence: 99%

The development and hepatotoxicity of acetaminophen: reviewing over a century of progress

McGill

Hinson

2020

Drug Metabolism Reviews

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Acetaminophen (APAP) was first synthesized in the 1800s, and came on the market approximately 65 years ago. Since then, it has become one of the most used drugs in the world. However, it is also a major cause of acute liver failure. Early investigations of the mechanisms of toxicity revealed that cytochrome P450 enzymes catalyze formation of a reactive metabolite in the liver that depletes glutathione and covalently binds to proteins. That work led to the introduction of N acetylcysteine (NAC) as an antidote for APAP overdose. Subsequent studies identified the reactive metabolite N-acetyl-p-benzoquinone imine, specific P450 enzymes involved, the mechanism of P450-mediated oxidation, and major adducted proteins. The mechanisms downstream of metabolism remain poorly understood but several events appear critical. These events include development of an initial oxidative stress, reactive nitrogen formation, altered calcium flux, JNK activation and mitochondrial translocation, inhibition of mitochondrial respiration, the mitochondrial permeability transition, and nuclear DNA fragmentation. Additional research is necessary to fill remaining gaps in our knowledge of the toxicity, such as the source of the initial oxidative stress, and to improve our understanding liver regeneration after APAP overdose. A better understanding of these mechanisms may lead to additional treatment options. Even though NAC is an excellent antidote, its effectiveness is limited to the first 16 hours following overdose.

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N-Hydroxyphenacetin as a precursor of 3-subst1tuted 4-hydroxyacetanilide metabolites of phenacetin

Cited by 33 publications

References 8 publications

What Are the Potential Sites of Protein Arylation by N-Acetyl-p-benzoquinone Imine (NAPQI)?

What Are the Potential Sites of Protein Arylation by N-Acetyl-p-benzoquinone Imine (NAPQI)?

Formation of a thiomethyl metabolite of phenacetin and acetaminophen in dogs and man

The development and hepatotoxicity of acetaminophen: reviewing over a century of progress

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