PXD066786-1

PXD066786 is an original dataset announced via ProteomeXchange.

Title	N-Acetyltransferase (NAT) 1 and NAT2 Enzyme Activities Drive Interindividual Variability in Sulfamethoxazole N-Acetylation
Description	Sulfamethoxazole (SMX) is associated with idiosyncratic drug induced liver injury (DILI), which remains difficult to predict. SMX is primarily metabolized by the N-acetyltransferases NAT1 and NAT2 to form N4-acetyl sulfamethoxazole (NA-SMX) and by cytochrome P450-mediated oxidation to form SMX-hydroxylamine. This study aimed to characterize SMX metabolism in vitro and investigate how NAT1 and NAT2 protein and activity variation influence NA-SMX formation. Using human liver microsomes (HLM), S9 fractions, and primary human hepatocytes (PHH), we quantified NA-SMX and other SMX metabolites. NA-SMX was the predominant metabolite in PHH, showing 4.2-fold variability across n = 26 donors. The NAT2 genotype-inferred acetylator phenotype did not reliably predict NA-SMX formation in six of nine slow acetylators, whose formation rate exceeded the mean rate of intermediate acetylators. However, NA-SMX formation was accurately predicted using the NAT2 probe substrate, sulfamethazine (SMZ), revealing significant differences between phenotype groups (p < 0.05). Activities of NAT1 and NAT2, as measured by p-aminobenzoic acid (PABA) and sulfamethazine (SMZ), respectively, significantly correlated with NA-SMX formation (r = 0.567, p = 0.007; r = 0.459, p = 0.036). The stronger correlation with NAT1 activity supports the relationship of NAT1 to SMX metabolism. Novel proteomic quantification of NAT2 revealed significant correlations between NAT2 protein levels and NAT2 activity (r = 0.823; p < 0.0001 and r = 0.734, p = 0.0002; for two peptides). This work provides quantitative insight into interindividual variability in SMX metabolism and highlights the importance of considering genetic and non-genetic, including proteomic, factors in SMX-induced DILI risk.
HostingRepository	PRIDE
AnnounceDate	2025-12-06
AnnouncementXML	Submission_2025-12-05_19:18:13.111.xml
DigitalObjectIdentifier
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Unsupported dataset by repository
PrimarySubmitter	John Fallon
SpeciesList	scientific name: Homo sapiens (Human); NCBI TaxID: NEWT:9606;
ModificationList	No PTMs are included in the dataset
Instrument	Q TRAP

Revision	Datetime	Status	ChangeLog Entry
0	2025-07-30 18:15:54	ID requested
⏵ 1	2025-12-05 19:18:13	announced

10.1016/J.DMD.2025.100195;

submitter keyword: None

Klarissa Jackson
contact affiliation	Division of Pharmacotherapy and Experimental Therapeutics, Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, USA
contact email	klarissa.jackson@unc.edu
lab head
John Fallon
contact affiliation	Eshelman School of Pharmacy, University of North Carolina at Chapel Hill
contact email	jfallon@email.unc.edu
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/2025/12/PXD066786

PRIDE project URI

• PRIDE
  1. PXD066786
     1. Label: PRIDE project
     2. Name: N-Acetyltransferase (NAT) 1 and NAT2 Enzyme Activities Drive Interindividual Variability in Sulfamethoxazole N-Acetylation