Nguyen Hai Duc, Vu Giang Huong, Hoang Linh Thuy, Kim Min-Sun
Department of Pharmacy, College of Pharmacy and Research Institute of Life and Pharmaceutical Sciences, Sunchon National University, Suncheon, 57922, Republic of Korea.
Division of Microbiology, Tulane National Primate Research Center, Tulane University, Covington, LA, 70433, USA.
Forensic Toxicol. 2025 Jan;43(1):33-45. doi: 10.1007/s11419-024-00702-3. Epub 2024 Sep 19.
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.
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.
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.
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.
我们旨在探索1,2 - 二乙酰苯（DAB）的代谢产物，并研究其有害影响、物理化学性质和生物活性，以及DAB本身的相关性质。
关键方法包括MetaTox、在线PASS、ADMESWISS、ADMETlab 2.0、分子对接和分子动力学模拟，以识别代谢产物、毒性作用、Lipinski规则标准、吸收、分布、代谢和排泄特性、与细胞色素（CYP）450同工型的相互作用以及DAB - 细胞色素复合物的稳定性。
共鉴定出13种DAB的代谢产物，涉及I相反应（脂肪族羟基化、环氧化、氧化脱氢和氢化）和II相反应（氧化硫酸化和甲基化）。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DAB代谢。所有研究的化合物均符合Lipinski规则，表明它们有可能作为毒性机制的诱导剂或激活剂。所研究化合物的物理化学参数和药代动力学与它们的有害影响一致，这些有害影响包括神经毒性、肾毒性、内分泌干扰和肝毒性，这是由于它们具有高胃肠道吸收能力和穿过血脑屏障的能力。各种CYP450同工型表现出不同的功能，并且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半胱天冬酶3和8的激活剂。DAB及其代谢产物还与细胞凋亡、氧化应激和神经内分泌干扰有关。
本研究预测了DAB及其代谢产物的毒性作用。有必要进一步研究它们对肝脏和肾脏等其他器官的影响，并验证我们的发现。
