Paracetamol metabolism and related genetic differences

Zhao, Lizi; Pickering, Gisèle

doi:10.3109/03602532.2010.527984

Cited by 108 publications

(104 citation statements)

References 105 publications

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“…While certain alleles have been identified that may modulate this risk, particularly those affecting the CYP 450 system, clinical trials to support these small studies are lacking (Zhao and Pickering 2011;Court et al 2014). In addition to identifying genetic variation within the CYP 450 system, recent evidence suggests that NAD(P)H:quinone oxidoreductase 1 (NQO1) plays a protective role by metabolizing NAPQI into a nontoxic hydroquinone.…”

Section: Risk Factorsmentioning

confidence: 99%

Acetaminophen hepatotoxicity: an updated review

2014

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Section: Risk Factorsmentioning

confidence: 99%

Acetaminophen hepatotoxicity: an updated review

2014

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“…Genetic variability could predispose some individuals to a higher risk of acetaminophen-induced liver injury than would be predicted based on the dose ingested, leading to ALF in a subset of these patients (Patel et al, 1992;Court et al, 2001;Rauchschwalbe et al, 2004;Zhao and Pickering, 2011). Candidate genes for this genetic variability would include those encoding enzymes important in the clearance of acetaminophen, including the UDP-glucuronosyltransferases (UGT) and sulfotransferases (SULT), and also the cytochrome P450 enzymes (CYP) responsible for converting acetaminophen to the hepatotoxic N-acetylparaquinoneimine (NAPQI).…”

Section: Introductionmentioning

confidence: 99%

Candidate Gene Polymorphisms in Patients with Acetaminophen-Induced Acute Liver Failure

et al. 2013

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Acetaminophen is a leading cause of acute liver failure (ALF). Genetic differences might predispose some individuals to develop ALF. In this exploratory study, we evaluated genotype frequency differences among patients enrolled by the ALF Study Group who had developed ALF either intentionally from a singletime-point overdose of acetaminophen (n = 78), unintentionally after chronic high doses of acetaminophen (n = 79), or from causes other than acetaminophen (n = 103). The polymorphisms evaluated included those in genes encoding putative acetaminophenmetabolizing enzymes (UGT1A1, UGT1A6, UGT1A9, UGT2B15, SULT1A1, CYP2E1, and CYP3A5) as well as CD44 and BHMT1. Individuals carrying the CYP3A5 rs776746 A allele were overrepresented among ALF patients who had intentionally overdosed with acetaminophen, with an odds ratio of 2.3 (95% confidence interval, 1.1-4.9; P = 0.034) compared with all other ALF patients.This finding is consistent with the enhanced bioactivation of acetaminophen by the CYP3A5 enzyme. Persons homozygous for the CD44 rs1467558 A allele were also overrepresented among patients who had unintentionally developed ALF from chronic acetaminophen use, with an odds ratio of 4.0 (1.0-17.2, P = 0.045) compared with all other ALF subjects. This finding confirms a prior study that found elevated serum liver enzyme levels in healthy volunteers with the CD44 rs1467558 AA genotype who had consumed high doses of acetaminophen for up to 2 weeks. However, both genetic associations were considered relatively weak, and they were not statistically significant after adjustment for multiple comparisons testing. Nevertheless, both CYP3A5 rs776746 and CD44 rs1467558 warrant further investigation as potential genomic markers of enhanced risk of acetaminopheninduced ALF.

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“…1) (Laine et al, 2009). NAPQI depletes glutathione (GSH) and subsequently causes covalent binding to important cellular proteins, initiates the formation of reactive oxygen species (ROS), promotes the release of proinflammatory cytokines such as tumor necrosis factor-a, and ultimately results in apoptosis and necrosis of hepatocytes (Tujios and Fontana, 2011;Zhao and Pickering, 2011). At subtoxic doses, NAPQI is inactivated by GSH conjugation, resulting in APAP cysteine and mercapturate conjugates (Laine et al, 2009).…”

Section: Introductionmentioning

confidence: 99%

MicroRNA-561 Promotes Acetaminophen-Induced Hepatotoxicity in HepG2 Cells and Primary Human Hepatocytes through Downregulation of the Nuclear Receptor Corepressor Dosage-Sensitive Sex-Reversal Adrenal Hypoplasia Congenital Critical Region on the X Chromosome, Gene 1 (DAX-1)

Yang

et al. 2013

Drug Metab Dispos

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One of the major mechanisms involved in acetaminophen (APAP)-induced hepatotoxicity is hepatocyte nuclear factor 4a (HNF4a)-mediated activation of pregnane X receptor (PXR) and constitutive androstane receptor (CAR). In the present study, we investigated the role of miR-561 and its target gene DAX-1 encoding a corepressor of HNF4a in the process of APAP-induced hepatotoxicity. We used both human hepatocellular liver carcinoma cell line (HepG2) cells and primary human hepatocytes in this study and monitored the levels of reactive oxygen species, lactate dehydrogenase, and glutathione. Our bioinformatics study suggests an association between miR-561 and DAX-1, but not HNF4a. Treatment of HepG2 cells with APAP significantly reduced the expression of DAX-1 in a concentration-dependent manner. miR-561 was induced by APAP treatment in HepG2 cells. Transfection of HepG2 cells with an miR-561 mimic exacerbated APAP-induced hepatotoxicity. HNF4a is physically associated with DAX-1 in HepG2 cells. A decreased protein level of DAX-1 by APAP treatment was also enhanced by miR-561 mimic transfection in HepG2 cells and primary human hepatocytes. The basal and APAP-induced expression of PXR and CAR was enhanced by miR-561 mimic transfection; however, transfection of HepG2 cells or primary human hepatocytes with a miR-561 inhibitor or DAX-1 small interfering RNA reversed these effects. Additionally, the chromatin immunoprecipitation assay revealed that recruitment of DAX-1 onto the PXR promoter was inversely correlated with the recruitment of peroxisome proliferator-activated receptor-a coactivator-1a and HNF4a on APAP treatment. These results indicate that miR-561 worsens APAP-induced hepatotoxicity via inhibition of DAX-1 and consequent transactivation of nuclear receptors.

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Paracetamol metabolism and related genetic differences

Cited by 108 publications

References 105 publications

Acetaminophen hepatotoxicity: an updated review

Acetaminophen hepatotoxicity: an updated review

Candidate Gene Polymorphisms in Patients with Acetaminophen-Induced Acute Liver Failure

MicroRNA-561 Promotes Acetaminophen-Induced Hepatotoxicity in HepG2 Cells and Primary Human Hepatocytes through Downregulation of the Nuclear Receptor Corepressor Dosage-Sensitive Sex-Reversal Adrenal Hypoplasia Congenital Critical Region on the X Chromosome, Gene 1 (DAX-1)

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