4.7 Article

N-acetyltransferase 2 genetic polymorphism modifies genotoxic and oxidative damage from new psychoactive substances

期刊

ARCHIVES OF TOXICOLOGY
卷 97, 期 1, 页码 189-199

出版社

SPRINGER HEIDELBERG
DOI: 10.1007/s00204-022-03383-2

关键词

New Psychoactive Substances; N-acetylation polymorphism; DNA damage; Oxidative damage; N-acetyltransferase 2

向作者/读者索取更多资源

The use of new psychoactive substances (NPS) as drugs of abuse, especially among youth and neglected communities, is common and increasingly popular. Genetic differences, particularly in Arylamine N-acetyltransferase 2 (NAT2) capacity, are likely to affect the long-term toxicity of these substances. This study investigates the gene-environment interaction between NAT2 polymorphism and toxicity after exposure to NPS, finding that N-acetylation and induction of genotoxic and oxidative damage are allele-dependent.
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.

作者

我是这篇论文的作者
点击您的名字以认领此论文并将其添加到您的个人资料中。

评论

主要评分

4.7
评分不足

次要评分

新颖性
-
重要性
-
科学严谨性
-
评价这篇论文

推荐

暂无数据
暂无数据