Unknown

Dataset Information

0

Rifampicin-activated human pregnane X receptor and CYP3A4 induction enhance acetaminophen-induced toxicity.


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 APAP-induced 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.

SUBMITTER: Cheng J 

PROVIDER: S-EPMC2712435 | BioStudies | 2009-01-01T00:00:00Z

REPOSITORIES: biostudies

Similar Datasets

2017-01-01 | S-EPMC5705655 | BioStudies
2014-01-01 | S-EPMC4006776 | BioStudies
1000-01-01 | S-EPMC3281537 | BioStudies
1000-01-01 | S-EPMC3101609 | BioStudies
2016-01-01 | S-EPMC4856301 | BioStudies
2016-01-01 | S-EPMC4778391 | BioStudies
2019-01-01 | S-EPMC6597219 | BioStudies
2018-01-01 | S-EPMC6062506 | BioStudies
1000-01-01 | S-EPMC5758662 | BioStudies
2021-01-01 | S-EPMC7452581 | BioStudies