PXD058085

PXD058085 is an original dataset announced via ProteomeXchange.

Title	Paracetamol metabolism by endothelial cells – potential mechanism underlying intravenous paracetamol-induced hypotension
Description	We have shown previously that a metabolite of acetaminophen (APAP), N-acetyl-p-benzoquinone imine (NAPQI), is a potent vasodilator, which could underlie the hypotension observed when APAP is administered intravenously. However, it is unknown whether APAP metabolism to NAPQI is possible in the vasculature. In this study, we examine the hypothesis that APAP is metabolized by cytochrome P450 enzymes within the endothelium, which may be accelerated in critically ill patients by the presence of elevated myeloperoxidase (MPO). Exposure of human coronary artery endothelial cells (HCAECs) to APAP resulted in the formation of protein-bound APAP adducts, together with a loss of metabolic activity. Proteomic analysis of HCAECs exposed to APAP showed upregulation of CYP20A1 and cytochrome P450 reductase (POR), together with proteins involved in the pentose phosphate pathway and maintaining redox homeostasis. Furthermore, proteomic analysis of mesenteric arteries and livers from rats administered intravenous APAP showed that APAP metabolism likely took place in the vascular wall and not in the liver. Moreover, similar proteomic pathway changes were identified in HCAECs and mesenteric arteries. Intracellular thiols were depleted in HCAECs upon APAP treatment, which was partially attenuated by ketoconazole, consistent with the involvement of cytochrome P450 enzymes (CYP) in the metabolism of APAP to a thiol-reactive metabolite such as NAPQI. Evidence was also obtained for the metabolism of APAP to a thiol-reactive intermediate by MPO, in accordance with NAPQI formation. Taken together, these data provide a putative mechanism to explain the presentation of hypotension in critically ill patients following IV APAP administration.
HostingRepository	PRIDE
AnnounceDate	2025-05-20
AnnouncementXML	Submission_2025-05-20_00:56:04.374.xml
DigitalObjectIdentifier
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Unsupported dataset by repository
PrimarySubmitter	Joakim Bastrup
SpeciesList	scientific name: Rattus rattus (Black rat); NCBI TaxID: 10117;
ModificationList	No PTMs are included in the dataset
Instrument	timsTOF Pro

Revision	Datetime	Status	ChangeLog Entry
0	2024-11-20 04:31:33	ID requested
⏵ 1	2025-05-20 00:56:04	announced

10.1016/J.PHRS.2024.107540;

submitter keyword: NAPQI,Acetaminophen, endothelium, CYP20A1, myeloperoxidase, paracetamol

Thomas Jepps
contact affiliation	Vascular Biology Group, Department of Biomedical Sciences, University of Copenhagen, Blegdamsvej 3, 2200 Copenhagen N, Denmark.
contact email	tjepps@sund.ku.dk
lab head
Joakim Bastrup
contact affiliation	Department of Biomedical Sciences, University of Copenhagen, Denmark
contact email	joakimbastrup@hotmail.dk
dataset submitter

Dataset FTP location NOTE: Most web browsers have now discontinued native support for FTP access within the browser window. But you can usually install another FTP app (we recommend FileZilla) and configure your browser to launch the external application when you click on this FTP link. Or otherwise, launch an app that supports FTP (like FileZilla) and use this address: ftp://ftp.pride.ebi.ac.uk/pride/data/archive/2025/05/PXD058085

PRIDE project URI

• PRIDE
  1. PXD058085
     1. Label: PRIDE project
     2. Name: Paracetamol metabolism by endothelial cells – potential mechanism underlying intravenous paracetamol-induced hypotension