Acetaminophen Usage Patterns and Concentrations of Glutathione and γ‐Glutamyl Transferase in Alcoholic Subjects

Seifert, Charles F.; Anderson, Douglas C.

doi:10.1592/phco.27.11.1473

Cited by 11 publications

(8 citation statements)

References 48 publications

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“…Chronic abusers of alcohol have reduced GSH levels 8 and the increased concentrations of gammaglutamyl transferase (GGT) observed frequently in alcohol abusers may be related to glutathione deficiency. 9 The timing of paracetamol ingestion may be an important factor. Studies in humans demonstrate that induction of CYP2E1 by alcohol is transient, lasting only a few days following cessation of alcohol exposure.…”

Section: Resultsmentioning

confidence: 99%

“…We administered the maximum approved dose of paracetamol to alcohol-abusing subjects for five consecutive days. Our subjects received paracetamol in a period of CYP2E1 induction and reduced plasma glutathione concentration, [8][9][10][11] thereby creating the conditions postulated to allow liver injury in patients who abuse alcohol. The results indicate that administration of paracetamol 4 g per day for 5 days to newly abstinent alcohol-abusing subjects was followed by a small increase in the serum ALT.…”

Section: Discussionmentioning

confidence: 99%

“…These groups are: (i) subjects who had serological + 21 were excluded due to baseline serum AST or ALT >200 IU/L, 7 were not able to receive their first dose within 12 h of their estimated time of sobriety, 1 patient had a baseline serum paracetamol level greater than 20 mcg/ml, 3 had a drinking binge duration less than 7 days, 1 presented with an undetectable blood alcohol level (BAL) by breath analyzer, 3 were judged unable to provide informed consent and 1 had an alcohol withdrawal seizure prior to their first dose evidence of hepatitis C infection; (ii) subjects who had an elevated ALT at baseline (from any cause) (iii) subjects who had an AST:ALT ratio >2 (suggestive of alcoholic hepatitis) and (iv) subjects with depressed GSH at baseline as evidenced by an increased GGT. 9 Independent two sample t-tests were used to determine if the mean change in ALT from day 0 to day 7 differed between groups. If the test for homogeneity of variances was significant, an unequal variance t-test was utilized.…”

Section: Statistical and Analytical Plansmentioning

confidence: 99%

See 2 more Smart Citations

The effects of paracetamol (acetaminophen) on hepatic tests in patients who chronically abuse alcohol – a randomized study

Dart

Green

Kuffner

et al. 2010

Aliment Pharmacol Ther

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Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Statistical and Analytical Plansmentioning

confidence: 99%

See 1 more Smart Citation

The effects of paracetamol (acetaminophen) on hepatic tests in patients who chronically abuse alcohol – a randomized study

Dart

Green

Kuffner

et al. 2010

Aliment Pharmacol Ther

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show abstract

“…GS-APAP, the result of a toxic metabolite that is converted into Cys-APAP or NAC-APAP, is predominantly excreted via the biliary route (Tokatli et al, 2007). These two secondary metabolites are converted by hepatic ␥-glutamyltranspeptidase (Seifert and Anderson, 2007) and excreted into urine. To dissect the APAP-metabolizing pathways in TgCYP3A4/hPXR mice, metabolomics analysis was carried out.…”

Section: Human Pxr and Cyp3a4 Regulate Apap Toxicitymentioning

confidence: 99%

Rifampicin-Activated Human Pregnane X Receptor and CYP3A4 Induction Enhance Acetaminophen-Induced Toxicity

Cheng¹,

Ma²,

Krausz³

et al. 2009

Drug Metab Dispos

115

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ABSTRACT:Acetaminophen (APAP) is safe at therapeutic levels but causes hepatotoxicity via N-acetyl-p-benzoquinone imine-induced oxidative stress upon overdose. To determine the effect of human (h) pregnane X receptor (PXR) activation and CYP3A4 induction on APAP-induced hepatotoxicity, mice humanized for PXR and CYP3A4 (TgCYP3A4/hPXR) were treated with APAP and rifampicin. Human PXR activation and CYP3A4 induction enhanced APAPinduced hepatotoxicity as revealed by hepatic alanine aminotransferase (ALT) and aspartate aminotransferase (AST) activities elevated in serum, and hepatic necrosis after coadministration of rifampicin and APAP, compared with APAP administration alone. In contrast, hPXR mice, wild-type mice, and Pxr-null mice exhibited significantly lower ALT/AST levels compared with TgCYP3A4/ hPXR mice after APAP administration. Toxicity was coincident with depletion of hepatic glutathione and increased production of hydrogen peroxide, suggesting increased oxidative stress upon hPXR activation. Moreover, mRNA analysis demonstrated that CYP3A4 and other PXR target genes were significantly induced by rifampicin treatment. Urinary metabolomic analysis indicated that cysteine-APAP and its metabolite S-(5-acetylamino-2-hydroxyphenyl)mercaptopyruvic acid were the major contributors to the toxic phenotype. Quantification of plasma APAP metabolites indicated that the APAP dimer formed coincident with increased oxidative stress. In addition, serum metabolomics revealed reduction of lysophosphatidylcholine in the APAP-treated groups. These findings demonstrated that human PXR is involved in regulation of APAP-induced toxicity through CYP3A4-mediated hepatic metabolism of APAP in the presence of PXR ligands.

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“…[22][23][24] Most studies regarding these interactions were focused on the metabolic interaction between ethanol and paracetamol. 27 The effects of acute ethanol intoxication on paracetamol hepatotoxicity are even more blurred. 27 The effects of acute ethanol intoxication on paracetamol hepatotoxicity are even more blurred.…”

Section: Introductionmentioning

confidence: 99%

The effects of ethanol on paracetamol-induced oxidative stress in mice liver

Mladenović¹,

Ninković²,

Vučević³

et al. 2013

JSCS

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The aim of our study was to investigate the effects of binge drinking on paracetamol induced oxidative stress in mice liver. Male Swiss mice were divided into groups: control; ethanol-treated group (E) in five subsequent doses of 2 g/kg by orogastric tube; paracetamol-treated group (P) in a dose of 300 mg/kg intraperitoneally; group that received paracetamol 12 hrs after the last dose of ethanol (PE). Blood and liver samples were collected for determination of oxidative stress parameters 6, 24 and 48 hrs after treatment. Prior binge drinking potentiated paracetamol-induced rise in liver malondialdehyde level 48 hours after treatment in comparison with P and E groups (17.14 ± 1.98 vs 13.14 ± 0.82 and 12.99 ± 1.18 μmol/L, p<0.01). Ethanol and paracetamol in combination induced a more pronounced decrease in liver GSH level than either of these substances alone at all time intervals (p<0.01). Total liver superoxide dismutase (SOD) activity was significantly lower in PE 48 hours after treatment in comparison with P and E groups (251.73 ± 80.63 vs 707.62 ± 179.92 and 1179.62 ± 147.94 U/mg prot., p<0.01). The lowest MnSOD activity in PE group was detected 48 hrs after treatment (86.52 ± 28.31; 41.13 ± 11.07 and 23.16 ± 5.18 U/mg prot. in P, E and PE groups, p<0.05, respectively). Prior binge ethanol drinking potentiates paracetamol-induced reduction of antioxidative capacity of hepatocytes due to GSH depletion and SOD activity reduction, simultaneously increasing lipid peroxidation caused by paracetamol. [Projekat Ministarstva nauke Republike Srbije, br. 175015

show abstract

Acetaminophen Usage Patterns and Concentrations of Glutathione and γ‐Glutamyl Transferase in Alcoholic Subjects

Cited by 11 publications

References 48 publications

The effects of paracetamol (acetaminophen) on hepatic tests in patients who chronically abuse alcohol – a randomized study

The effects of paracetamol (acetaminophen) on hepatic tests in patients who chronically abuse alcohol – a randomized study

Rifampicin-Activated Human Pregnane X Receptor and CYP3A4 Induction Enhance Acetaminophen-Induced Toxicity

The effects of ethanol on paracetamol-induced oxidative stress in mice liver

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