Genetic heterogeneity among slow acetylator N-acetyltransferase 2 phenotypes in cryopreserved human hepatocytes

Archives of Toxicology
M A Doll, D W Hein

Abstract

Genetic polymorphisms in human N-acetyltransferase 2 (NAT2) modify the metabolism of numerous drugs and carcinogens. These genetic polymorphisms modify both drug efficacy and toxicity and cancer risk associated with carcinogen exposure. Previous studies have suggested phenotypic heterogeneity among different NAT2 slow acetylator genotypes. NAT2 phenotype was investigated in vitro and in situ in samples of human hepatocytes obtained from various NAT2 slow and intermediate NAT2 acetylator genotypes. NAT2 gene dose response (NAT2*5B/*5B > NAT2*5B/*6A > NAT2*6A/*6A) was observed towards the N-acetylation of the NAT2-specific drug sulfamethazine by human hepatocytes both in vitro and in situ. N-acetylation of 4-aminobiphenyl, an arylamine carcinogen substrate for both N-acetyltransferase 1 and NAT2, showed the same trend both in vitro and in situ although the differences were not significant (p > 0.05). The N-acetylation of the N-acetyltransferase 1-specific substrate p-aminobenzoic acid did not follow this trend. In comparisons of NAT2 intermediate acetylator genotypes, differences in N-acetylation between NAT2*4/*5B and NAT2*4/*6B hepatocytes were not observed in vitro or in situ towards any of these substrates. These results furt...Continue Reading

References

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Citations

Oct 12, 2017·Drug Metabolism and Disposition : the Biological Fate of Chemicals·Cecily E AllenDavid W Hein
Dec 1, 2017·Archives of Toxicology·Silvia Selinski
Jul 4, 2018·Archives of Toxicology·Daniela Fernanda González Leiva
Oct 24, 2020·Expert Opinion on Drug Metabolism & Toxicology·David W Hein, Lori M Millner
Nov 3, 2020·Clinical Pharmacology and Therapeutics·Paola NicolettiGuruprasad P Aithal
Apr 11, 2021·Clinical Pharmacology and Therapeutics·Frank R WendtRenato Polimanti

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Methods Mentioned

BETA
acetylator
protein assay
genotyping
PCR
acetylation

Software Mentioned

Primer [UNK]

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