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Genetic heterogeneity among slow acetylator N-acetyltransferase 2 phenotypes in cryopreserved human hepatocytes
Ist Teil von
Archives of toxicology, 2017-07, Vol.91 (7), p.2655-2661
Ort / Verlag
Berlin/Heidelberg: Springer Berlin Heidelberg
Erscheinungsjahr
2017
Quelle
MEDLINE
Beschreibungen/Notizen
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 further support phenotypic heterogeneity among
NAT2
slow acetylator genotypes, consistent with differential risks of drug failure or toxicity and cancer associated with carcinogen exposure.