The mechanism of prevention of paracetamol-induced hepatotoxicity by 3,5-dialkyl substitution

Straat, R. van de; Vries, J. de; Debets, Alexander J.; Vermeulen, Nico

doi:10.1016/0006-2952(87)90132-8

Cited by 73 publications

(23 citation statements)

References 23 publications

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“…Although contradictory data have been reported regarding the oxidative stress hypothesis for acetaminophen toxicity (88 -90), it is a fact that NAPQI, the major reactive metabolite of acetaminophen, is a potent oxidant as well as an electrophile. Oxidative damage in liver cells has been demonstrated both in vivo (43,82,(91)(92)(93)(94)(95)(96) and in vitro (89,(97)(98)(99)(100). The modification of detoxification enzymes discovered in this work may compromise their function and thus potentiate the toxicity of acetaminophen by further breaking down the cell's normal defense mechanism against oxidative stress caused by NAPQI and also possibly by endogenous reactive oxygen species (101).…”

Section: Discussionmentioning

confidence: 85%

Identification of the Hepatic Protein Targets of Reactive Metabolites of Acetaminophen in Vivoin Mice Using Two-dimensional Gel Electrophoresis and Mass Spectrometry

Qiu¹,

Benet²,

Burlingame³

1998

Journal of Biological Chemistry

298

232

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Liver toxicity following an overdose of acetaminophen is frequently considered a model for drug-induced hepatotoxicity. Extensive studies over many years have established that such toxicity is well correlated with liver protein arylation by acetaminophen metabolites. Identification of protein targets for covalent modifications is a challenging but necessary step in understanding how covalent binding could lead to liver toxicity. Previous approaches suffered from technical limitations, and thus over the last 10 years heroic efforts were required to determine the identity of only a few target proteins. We present a new mass spectrometry-based strategy for identification of all target proteins that now provides a comprehensive survey of the suite of liver proteins modified. After administration of radiolabeled acetaminophen to mice, the proteins in the liver tissue lysate were separated by two-dimensional polyacrylamide gel electrophoresis. In-gel digestion of the radiolabeled gel spots gave a set of tryptic peptides, which were analyzed by matrix-assisted laser desorption ionization mass spectrometry. Interrogation of data bases based on experimentally determined molecular weights of peptides and product ion tags from postsource decay mass spectra was employed for the determination of the identities of modified liver proteins. Using this method, more than 20 new drug-labeled proteins have been identified.

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Section: Discussionmentioning

confidence: 85%

Identification of the Hepatic Protein Targets of Reactive Metabolites of Acetaminophen in Vivoin Mice Using Two-dimensional Gel Electrophoresis and Mass Spectrometry

Qiu¹,

Benet²,

Burlingame³

1998

Journal of Biological Chemistry

298

232

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“…Therefore, several attempts to reduce the adverse effects of APAP or ASA have been conducted (Buckley et al, 1999;Kalabis and Wells, 1990;Prescott and Critchley, 1983;van Bree et al, 1989;van de Straat et al, 1987;Wu et al, 2008) in which treatment of APAP or ASA in combination with other compounds such as caffeine or codeine has been suggested for increasing analgesic potency and decreasing the risks of complications (Bach et al, 1998;Engelhardt and Homma, 1996;Engelhardt et al, 1997). In this regard, we also examined the effects of decursinol, which previously had been announced as having a potent analgesic property, on ASA and APAP-induced analgesia, respectively.…”

Section: Discussionmentioning

confidence: 99%

The analgesic effect of decursinol

Seo

Kwon²,

Park

et al. 2009

Arch. Pharm. Res.

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Although decursinol, which is one of the coumarins purified from the dried roots of Angelica gigas Nakai, was previously demonstrated to have antinociceptive effects on various mouse pain models such as tail-flick, hot-plate, formalin, writhing, and several cytokine-induced pain tests, the possible involvement of its analgesic effects and non-steroidal anti-inflammatory drugs (NSAIDs) has not been clearly elucidated yet. In this study, we characterized the possible interaction between decursinol and aspirin or acetaminophen in the writhing test. The antinociceptive effects of decursinol were observed at an orally-administered dose of 50 mg/kg but not at 25 or 10 mg/kg. In addition, the analgesic effects of aspirin (ASA) and acetaminophen (APAP) were shown at an orally-administered dose of 200 mg/kg but not at 50 or 100 mg/kg. We examined the effects of decursinol on the ASA or APAP at sub-analgesic doses. Although the co-administration of decursinol and ASA did not show any differences at doses of 10 or 25 mg/kg and 50 or 100 mg/kg, respectively, synergistic effects between decursinol and APAP were observed in the group of decursinol (25 mg/kg) and APAP (100 mg/kg) co-administration. These results indicated that the analgesic effect of decursinol might be involved in supraspinal cyclooxygenase regulation that might be overlapped with APAP-induced analgesic mechanisms rather than systemic or peripheral prostaglandin modulation.

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“…Indeed, the radical species proposed by Loew and Goldblum (1984) with high electron spin density located on positions 3 and 5 of the ring would be susceptible to attack by cellular nucleophiles, particularly GSH, at these positions. Methylation of position 3 and 5 on the ring has been shown to prevent APAP toxicity in isolated hepatocytes by removing the reactivity towards GSH and thiol groups on proteins ( Van de Straat et al 1987). A similar treatment of PAP would predictably prevent nephrotoxicity.…”

Section: Effect Of Biliary Cannulation On Pap-induced Nephrotoxicitymentioning

confidence: 99%

Effects of biliary cannulation and buthionine sulphoximine pretreatment on the nephrotoxicity of para-aminophenol in the Fischer 344 rat

Gartland

Eason²,

Bonner³

et al. 1990

Arch Toxicol

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The effects of a glutathione depletor, buthionine sulphoximine (BSO) and biliary cannulation on the nephrotoxicity of p-aminophenol (PAP) have been investigated in the F344 rat. Pretreatment with BSO completely protected against the nephrotoxicity of a 50 mg/kg dose of PAP, assessed by clinical chemistry, renal histopathology, and 1H-NMR urinalysis. Biliary cannulation partially protects against nephrotoxicity induced by 100 mg/kg PAP. These data suggest that the nephrotoxicity of PAP may be due in part to the formation of a proximate toxic metabolite in the liver which is excreted in the bile, subsequently reabsorbed and transported via the systemic circulation to the kidney where the toxic effects occur.

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The mechanism of prevention of paracetamol-induced hepatotoxicity by 3,5-dialkyl substitution

Cited by 73 publications

References 23 publications

Identification of the Hepatic Protein Targets of Reactive Metabolites of Acetaminophen in Vivoin Mice Using Two-dimensional Gel Electrophoresis and Mass Spectrometry

Identification of the Hepatic Protein Targets of Reactive Metabolites of Acetaminophen in Vivoin Mice Using Two-dimensional Gel Electrophoresis and Mass Spectrometry

The analgesic effect of decursinol

Effects of biliary cannulation and buthionine sulphoximine pretreatment on the nephrotoxicity of para-aminophenol in the Fischer 344 rat

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