Metabolic effects of heterocyclic amines on insulin‑induced AKT phosphorylation and gluconeogenic gene expression are modified by N -acetyltransferase 2 genetic polymorphism.

IF 1.7 3区 医学 Q4 BIOTECHNOLOGY & APPLIED MICROBIOLOGY
Pharmacogenetics and genomics Pub Date : 2025-06-01 Epub Date: 2025-01-29 DOI:10.1097/FPC.0000000000000559
Kennedy M Walls, Jonathan Y Joh, Madeline M Martinez, Kyung U Hong, David W Hein
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引用次数: 0

Abstract

Objective: Heterocyclic amines (HCAs) are mutagens and carcinogens primarily generated when cooking meat at high temperatures or until well-done, and their major metabolic pathway includes hepatic N -hydroxylation via CYP1A2 followed by O -acetylation via N -acetyltransferase 2 (NAT2). NAT2 expresses a well-defined genetic polymorphism in humans resulting in rapid and slow acetylators. Recent epidemiological studies reported significant associations between dietary HCA exposure and insulin resistance and type II diabetes.

Methods: We assessed the effect of some of the most common HCAs found in cooked meat, 2-amino-3,4-dimethylimidazo[4,5-f]quinoline, 2-amino-3,8-dimethylimidazo[4,5-f]quinoxaline, and 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine, on insulin signaling and gluconeogenic gene expression in cryopreserved human hepatocytes characterized by their NAT2 genotype and phenotype to investigate the role of NAT2 genetic polymorphism in HCA-induced metabolic dysregulation.

Results: HCA treatment significantly reduced insulin-induced protein kinase B phosphorylation and significantly increased expression of genes involved in gluconeogenesis ( G6PC , PCK1 , FOXO1 , and PPARA ) in cryopreserved human hepatocytes from rapid but not from slow acetylators.

Conclusion: The findings suggest that NAT2 genetic polymorphism modifies HCA-induced insulin resistance and gluconeogenic gene expression, implying that individuals with rapid acetylator phenotype may be at greater risk of dysregulated glucose homeostasis following exposure to HCAs.

n -乙酰基转移酶2基因多态性修饰了杂环胺对胰岛素诱导的AKT磷酸化和糖异生基因表达的代谢作用。
目的:杂环胺(Heterocyclic amines, HCAs)是一种诱变剂和致癌物,主要在肉类高温烹调或熟透时产生,其主要代谢途径是通过CYP1A2进行肝脏n -羟基化,然后通过n -乙酰转移酶2 (N-acetyltransferase 2, NAT2)进行o -乙酰化。NAT2在人类中表达明确的遗传多态性,导致快速和缓慢的乙酰化。最近的流行病学研究报告了饮食中HCA暴露与胰岛素抵抗和II型糖尿病之间的显著关联。方法:我们评估了在熟肉中发现的一些最常见的HCAs, 2-氨基-3,4-二甲基咪唑[4,5-f]喹啉,2-氨基-3,8-二甲基咪唑[4,5-f]喹啉和2-氨基-1-甲基-6-苯基咪唑[4,5-b]吡啶对低温保存的人肝细胞中以其NAT2基因型和表型为特征的胰岛素信号传导和糖异生基因表达的影响,以研究NAT2基因多态性在hca诱导的代谢失调中的作用。结果:HCA处理显著降低了胰岛素诱导的蛋白激酶B磷酸化,并显著增加了低温保存的人肝细胞中糖异生相关基因(G6PC、PCK1、FOXO1和PPARA)的表达,而不是缓慢乙酰化。结论:研究结果表明,NAT2基因多态性改变了hca诱导的胰岛素抵抗和糖异生基因的表达,这意味着快速乙酰化表型的个体在暴露于hca后可能面临更大的葡萄糖稳态失调风险。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
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来源期刊
Pharmacogenetics and genomics
Pharmacogenetics and genomics 医学-生物工程与应用微生物
CiteScore
3.20
自引率
3.80%
发文量
47
审稿时长
3 months
期刊介绍: ​​​​Pharmacogenetics and Genomics is devoted to the rapid publication of research papers, brief review articles and short communications on genetic determinants in response to drugs and other chemicals in humans and animals. The Journal brings together papers from the entire spectrum of biomedical research and science, including biochemistry, bioinformatics, clinical pharmacology, clinical pharmacy, epidemiology, genetics, genomics, molecular biology, pharmacology, pharmaceutical sciences, and toxicology. Under a single cover, the Journal provides a forum for all aspects of the genetics and genomics of host response to exogenous chemicals: from the gene to the clinic.
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