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N-acetyltransferase 2 genetic polymorphism modifies genotoxic and oxidative damage from new psychoactive substances
Ist Teil von
Archives of toxicology, 2023-01, Vol.97 (1), p.189-199
Ort / Verlag
Berlin/Heidelberg: Springer Berlin Heidelberg
Erscheinungsjahr
2023
Link zum Volltext
Quelle
SpringerLink (Online service)
Beschreibungen/Notizen
The use of new psychoactive substances (NPS) as drugs of abuse is common and increasingly popular, particularly among youth and neglected communities. Recent studies have reported acute toxic effects from these chemicals; however, their long-term toxicity is unknown. Genetic differences between individuals likely affect the toxicity risk. Arylamine
N
-acetyltransferase 2 (
NAT2
) capacity differs among individuals due to genetic inheritance. The goal of the present study is to investigate the gene–environment interaction between
NAT2
polymorphism and toxicity after exposure to these chemicals. We measured
N
-acetylation by human
NAT1
and
NAT2
and found that
N
-acetylation of NPS is carried out exclusively by
NAT2
. Differences in
N
-acetylation between
NAT2*4
(reference allele) and
NAT2*5B
(common variant allele) were highly significant (
p
< 0.0001). Using DNA repair-deficient genetically engineered Chinese hamster ovary (CHO cells), expressing human
CYP1A2
and either
NAT2*4
or
NAT2*5B
, we measured the induction of DNA double-strand breaks (
γ
H2Ax) following treatment of the CHO cells with increasing concentrations of NPS. The induction of
γ
H2Ax showed a
NAT2
allele-dependent response, higher in the
NAT2*4
vs
NAT2*5B
alleles (
p
< 0.05). Induction of oxidative stress (ROS/RNS) was evaluated; we observed
NAT2
allele-dependent response for all compounds in concentrations as low as 10
μ
M, where
NAT2*4
showed increased ROS/RNS vs
NAT2*5B
(
p
< 0.05). In summary, NPS are
N
-acetylated by
NAT2
at rates higher in cells expressing
NAT2*4
than
NAT2*5B
. Exposure to psychoactive chemicals results in genotoxic and oxidative damage that is modified by the
NAT2
genetic polymorphism.