Yamazoe Yasushi, Murayama Norie, Kawamura Tomoko, Yamada Takashi
Division of Drug Metabolism and Molecular Toxicology, Graduate School of Pharmaceutical Sciences, Tohoku University, 6-3 Aramaki-Aoba, Aoba-ku, Sendai, 980-8578, Japan.
Division of Risk Assessment, Center for Biological Safety and Research, National Institute of Health Sciences, 3-25-26 Tonomachi, Kawasaki-ku, Kawasaki, 210-9501, Japan.
Genes Environ. 2023 Aug 7;45(1):22. doi: 10.1186/s41021-023-00275-4.
Understanding of metabolic processes is a key factor to evaluate biological effects of carcinogen and mutagens. Applicability of fused-grid Template* systems of CYP enzymes (Drug Metab Pharmacokinet 2019, 2020, 2021, and 2022) was tested for three phenomena. (1) Possible causal relationships between CYP-mediated metabolisms of β-naphthoflavone and 3-methylcholanthrene and the high inducibility of CYP enzymes were examined. Selective involvement of non-constitutive CYP1A1, but not constitutive CYP1A2, was suggested on the oxidative metabolisms of efficient inducers, β-naphthoflavone and 3-methylcholanthrene. These results supported the view of the causal link of their high inducibility with their inefficient metabolisms due to the lack of CYP1A1 in livers at early periods after the administration of both inducers. (2) Clear differences exist between human and rodent CYP1A1 enzymes on their catalyses with heterocyclic amines, dioxins and polyaromatic hydrocarbons (PAHs). Reciprocal comparison of simulation results with experimental data suggested the rodent specific site and distinct sitting-preferences of ligands on Template for human and rodent CYP1A1 enzymes. (3) Enhancement of metabolic activation and co-mutagenicity have been known as phenomena associated with Salmonella mutagenesis assay. Both the phenomena were examined on CYP-Templates in ways of simultaneous bi-molecule bindings of distinct ligands as trigger and pro-metabolized molecules. α-Naphthoflavone and norharman served consistently as trigger-molecules to support the oxidations of PAHs and arylamines sitting simultaneously as pro-metabolized molecules on Templates of CYP1A1, CYP1A2 and CYP3A4. These CYP-Template simulation systems with deciphering capabilities are promising tools to understand the mechanism basis of metabolic activations and to support confident judgements in safety assessments.
了解代谢过程是评估致癌物和诱变剂生物学效应的关键因素。针对三种现象测试了CYP酶融合网格模板*系统的适用性（《药物代谢与药代动力学》，2019年、2020年、2021年和2022年）。（1）研究了CYP介导的β-萘黄酮和3-甲基胆蒽代谢与CYP酶高诱导性之间可能的因果关系。结果表明，在高效诱导剂β-萘黄酮和3-甲基胆蒽的氧化代谢中，非组成型CYP1A1而非组成型CYP1A2有选择性地参与。这些结果支持了这样一种观点，即由于在两种诱导剂给药后的早期肝脏中缺乏CYP1A1，它们的高诱导性与其低效代谢之间存在因果联系。（2）人类和啮齿动物的CYP1A1酶在催化杂环胺、二恶英和多环芳烃（PAHs）方面存在明显差异。模拟结果与实验数据的相互比较表明了啮齿动物特有的位点以及配体在人类和啮齿动物CYP1A1酶模板上不同的结合偏好。（3）代谢活化增强和共诱变已被认为是与沙门氏菌诱变试验相关的现象。通过将不同配体作为触发分子和前代谢分子同时进行双分子结合的方式，在CYP模板上研究了这两种现象。α-萘黄酮和去甲哈尔满一直作为触发分子，支持多环芳烃和芳胺在CYP1A1、CYP1A2和CYP3A4模板上同时作为前代谢分子的氧化。这些具有解密能力的CYP模板模拟系统是理解代谢活化机制基础以及在安全性评估中支持可靠判断的有前途的工具。
