Role of polymorphic and monomorphic human arylamine N-acetyltransferases in determining sulfamethoxazole metabolism

Cribb, Alastair E.; Nakamura, Hidefumi; Grant, Denis M.; Miller, Margaret A.; Spielberg, Stephen P.

doi:10.1016/0006-2952(93)90280-a

Cited by 62Pharmacogenetics and Drug MetabolismDrug-Induced Adverse ReactionsDrug-Induced Hepatotoxicity and Protection

Role of polymorphic and monomorphic human arylamine N-acetyltransferases in determining sulfamethoxazole metabolism

Cribb, Alastair E., Nakamura, Hidefumi, Grant, Denis M., Miller, Margaret A., Spielberg, Stephen P.·1993·Biochemical Pharmacology

DOI 10.1016/0006-2952(93)90280-a

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Abstract

Sulfonamides are associated with a variety of adverse reactions, some of which have been linked with the classical acetylator phenotypes. Although the slow acetylator phenotype has been identified as a risk factor for hypersensitivity reactions to sulfamethoxazole (SMX), the disposition of this compound appears not to be affected by the acetylation polymorphism in vivo in humans. We therefore investigated the acetylation of SMX by monomorphic (NAT1) and polymorphic (NAT2) arylamine N-acetyltransferases in humans with the objective of determining their role in the metabolism of SMX. SMX was acetylated by both NAT1 and NAT2. Km values determined in hepatic cytosol for NAT1- and NAT2-mediated acetylation of SMX were 1.2 mM and approximately 5 mM, respectively, at an acetyl coenzyme A concentration of 100 microM. Mononuclear leukocytes, which contain only NAT1, had a Km value of 1.2 mM. Km values determined with recombinant NAT1 and NAT2 proteins expressed in Escherichia coli were 1.5 mM and approximately 15 mM, respectively. The higher affinity of NAT1 for SMX indicates that acetylation by this enzyme will predominate at therapeutic plasma concentrations, in agreement with the observed in vivo monomorphic acetylation of SMX. NAT1 may be the primary determinant of SMX systemic metabolic clearance. However, in the hepatocyte NAT2 variation may be an important competitive pathway which influences the extent of oxidative metabolism of SMX to its reactive hydroxylamine metabolite. Therefore, variation in both monomorphic and polymorphic N-acetyltransferases may play a role in determining susceptibility to sulfamethoxazole toxicity.

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NAT1 and NAT2 exist with multiple variants, which can alter their ability to acetylate SMX by either enhancing or reducing their acetylation capacity.
“NAT1 and NAT2 exist with multiple variants, which can alter their ability to acetylate SMX by either enhancing or reducing their acetylation capacity.25”
From N-Acetyltransferase (NAT) 1 and NAT2 Enzyme Activities Drive Interindividual Variability in Sulfamethoxazole N-Acetylation (2025) · cites this paper as [25]
NAT2 remains a key contributor to NA-SMX formation, evidenced by correlation of NAT2 activity to NA-SMX formation in this study and a previous study in hepatic cytosol.
“NAT2 remains a key contributor to NA-SMX formation as evidenced by the correlation of NAT2 activity to NA-SMX formation in this study and a previous study in hepatic cytosol, but further studies are needed to quantify the specific contributions of NAT1 and NAT2 through determination of fraction metabolized, or Fm values, by each enzyme.25”
From N-Acetyltransferase (NAT) 1 and NAT2 Enzyme Activities Drive Interindividual Variability in Sulfamethoxazole N-Acetylation (2025) · cites this paper as [25]
Recombinant NAT1 has a Km of 1.5 mM for SMX N4-acetylation, while NAT2-mediated SMX N4-acetylation has a Km of approximately 15 mM.
“A previous study showed a 1.5 mM Km for SMX N4-acetylation by recombinant NAT1 protein, whereas the Km of NAT2-mediated SMX N4-acetylation was approximately 15 mM.25”
From N-Acetyltransferase (NAT) 1 and NAT2 Enzyme Activities Drive Interindividual Variability in Sulfamethoxazole N-Acetylation (2025) · cites this paper as [25]
Both NAT1 and NAT2 are involved in SMX acetylation, but the extent of this involvement is not well characterized.
“The involvement of both NAT1 and NAT2 in SMX acetylation has been previously reported; however, the extent of this involvement is not well characterized.25”
From N-Acetyltransferase (NAT) 1 and NAT2 Enzyme Activities Drive Interindividual Variability in Sulfamethoxazole N-Acetylation (2025) · cites this paper as [25]

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Authors: Cribb, A. E., Nakamura, H., Grant, D. M., Miller, M. A., & Spielberg, S. P.
Affiliations: University of Toronto (CA)
Corresponding author: Spielberg, Stephen P.
ORCID: Cribb, Alastair E.
Nakamura, Hidefumi
Grant, Denis M.
Venue: Biochemical Pharmacology
Publisher: Elsevier BV
Published: 1993-03
Volume: 45
Issue: 6
Pages: 1277-1282
ISSN: 0006-2952 (ISSN-L)
DOI: 10.1016/0006-2952(93)90280-a
OpenAlex: W1969299179
Cited by: 62
References: 29
Citations by year: 2025: 5 · 2022: 1 · 2021: 2 · 2020: 4 · 2018: 4 · 2017: 2 · 2016: 2 · 2014: 1 · 2012: 2
FWCI: 4.21
Type: journal article
Language: en
Open access: closed
Licence: www.elsevier.com/tdm/userlicense/1.0/ (tdm)
Locations: Biochemical Pharmacology (publishedVersion)
PubMed (publishedVersion)
Topics: Life Sciences › Pharmacology, Toxicology and Pharmaceutics › Pharmacology › Pharmacogenetics and Drug Metabolism
Health Sciences › Medicine › Pharmacology › Drug-Induced Adverse Reactions
Life Sciences › Pharmacology, Toxicology and Pharmaceutics › Pharmacology › Drug-Induced Hepatotoxicity and Protection
Keywords: sulfamethoxazole, arylamine N-acetyltransferase 1, arylamine N-acetyltransferase 2, drug metabolism, acetylator phenotype, sulfonamide hypersensitivity, hydroxylamine metabolites, metabolic clearance, mononuclear leukocytes, liver cytosol, sulfonamide toxicity
MeSH terms: Acetylation, Acetyltransferases, Arylamine N-Acetyltransferase, Humans, Kinetics, Liver, Recombinant Proteins, Sulfamethoxazole

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Role of polymorphic and monomorphic human arylamine N-acetyltransferases in determining sulfamethoxazole metabolism

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