N-acetyltransferase (NAT) 1 and NAT2 enzyme activities drive interindividual variability in sulfamethoxazole N-acetylation.

ABSTRACT: Sulfamethoxazole (SMX) is associated with idiosyncratic drug-induced liver injury, which remains difficult to predict. SMX is metabolized by N-acetyltransferases (NAT1/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 variation influences NA-SMX formation, including the relationship between NAT2 protein levels and metabolite formation. Human liver microsomes, S9 fractions, and primary human hepatocytes were used to generate SMX metabolites. NA-SMX was the most abundant metabolite in primary human hepatocytes, showing 4.2-fold variability across n = 26 donors. Interestingly, NAT2 genotype-inferred acetylator phenotype did

SUBMITTER: Lanphier RM 

PROVIDER: S-EPMC12861138 | biostudies-literature | 2025 Dec

REPOSITORIES: biostudies-literature