Elucidation of toxic effects of 1,2-diacetylbenzene: an in silico study

IF 2.8 4区 医学 Q2 TOXICOLOGY
Hai Duc Nguyen, Giang Huong Vu, Linh Thuy Hoang, Min-Sun Kim
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引用次数: 0

Abstract

Purpose

We aimed to explore the metabolite products of 1,2-diacetylbenzene (DAB) and investigate their harmful effects, physicochemical properties, and biological activities, along with those of DAB itself.

Methods

Key approaches included MetaTox, PASS online, ADMESWISS, ADMETlab 2.0, molecular docking, and molecular dynamic simulation to identify metabolites, toxic effects, Lipinski’s rule criteria, absorption, distribution, metabolism, and excretion properties, interactions with cytochrome (CYP) 450 isoforms, and the stability of the DAB-cytochrome complex.

Results

A total of 13 metabolite products from DAB were identified, involving Phase I reactions (aliphatic hydroxylation, epoxidation, oxidative dehydrogenation, and hydrogenation) and Phase II reactions (oxidative sulfation and methylation). Molecular dynamics and modeling revealed a stable interaction between CYP1A2 and DAB, suggesting the involvement of CYP1A2 in DAB metabolism. All studied compounds adhered to Lipinski’s rule, indicating their potential as inducers or activators of toxic mechanisms. The physicochemical parameters and pharmacokinetics of the investigated compounds were consistent with their harmful effects, which included neurotoxic, nephrotoxic, endocrine disruptor, and hepatotoxic consequences due to their high gastrointestinal absorption and ability to cross the blood–brain barrier. Various CYP450 isoforms exhibited different functions, and the compounds were found to act as superoxide dismutase inhibitors, neuropeptide Y2 antagonists, glutaminase inhibitors, and activators of caspases 3 and 8. DAB and its metabolites were also associated with apoptosis, oxidative stress, and neuroendocrine disruption.

Conclusion

The toxic effects of DAB and its metabolites were predicted in this study. Further research is warranted to explore their effects on other organs, such as the liver and kidneys, and to validate our findings.

Abstract Image

阐明 1,2-二乙酰基苯的毒性效应:硅学研究
目的 我们旨在探索 1,2-二乙酰苯(DAB)的代谢产物,并研究其有害作用、理化性质和生物活性,以及 DAB 本身的有害作用、理化性质和生物活性。0、分子对接和分子动力学模拟来确定代谢物、毒性作用、利平斯基规则标准、吸收、分布、代谢和排泄特性、与细胞色素(CYP)450 同工酶的相互作用以及 DAB-细胞色素复合物的稳定性。结果 共确定了 13 种 DAB 代谢产物,涉及 I 期反应(脂肪族羟化、环氧化、氧化脱氢和氢化)和 II 期反应(氧化硫化和甲基化)。分子动力学和建模显示 CYP1A2 与 DAB 之间存在稳定的相互作用,表明 CYP1A2 参与了 DAB 的代谢。所有研究化合物都符合利宾斯基规则,表明它们有可能成为毒性机制的诱导剂或激活剂。所研究化合物的理化参数和药代动力学与它们的有害作用相一致,其中包括神经毒性、肾毒性、内分泌干扰素和肝毒性,这是因为它们具有较高的胃肠道吸收能力和穿越血脑屏障的能力。各种 CYP450 同工酶表现出不同的功能,发现这些化合物可作为超氧化物歧化酶抑制剂、神经肽 Y2 拮抗剂、谷氨酰胺酶抑制剂以及 Caspases 3 和 8 激活剂。DAB 及其代谢物还与细胞凋亡、氧化应激和神经内分泌紊乱有关。我们有必要进一步研究它们对其他器官(如肝脏和肾脏)的影响,并验证我们的研究结果。
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
Forensic Toxicology
Forensic Toxicology TOXICOLOGY-
CiteScore
5.80
自引率
9.10%
发文量
40
审稿时长
3 months
期刊介绍: The journal Forensic Toxicology provides an international forum for publication of studies on toxic substances, drugs of abuse, doping agents, chemical warfare agents, and their metabolisms and analyses, which are related to laws and ethics. It includes original articles, reviews, mini-reviews, short communications, and case reports. Although a major focus of the journal is on the development or improvement of analytical methods for the above-mentioned chemicals in human matrices, appropriate studies with animal experiments are also published. Forensic Toxicology is the official publication of the Japanese Association of Forensic Toxicology (JAFT) and is the continuation of the Japanese Journal of Forensic Toxicology (ISSN 0915-9606).
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