Abstract
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 (\(\gamma\)H2Ax) following treatment of the CHO cells with increasing concentrations of NPS. The induction of \(\gamma\)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 \(\mu\)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.
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Research reported in this publication/presentation was supported by the National Institute of Environmental Health Sciences of the National Institutes of Health under Award Number P30ES030283. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.
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RASG: conceived and designed study, performed research, analyzed data, interpretation of the data, contributed new methods and models, and wrote the manuscript. MAD: performed research, analyzed data, interpretation of the data, contributed new methods and models, and edited the manuscript. DWH: conceived and designed study, interpretation of the data, and edited the manuscript.
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Salazar-González, R.A., Doll, M.A. & Hein, D.W. N-acetyltransferase 2 genetic polymorphism modifies genotoxic and oxidative damage from new psychoactive substances. Arch Toxicol 97, 189–199 (2023). https://doi.org/10.1007/s00204-022-03383-2
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DOI: https://doi.org/10.1007/s00204-022-03383-2