Gut bacterial O-demethylation

肠道细菌O-去甲基化

• 批准号: 10477476
• 负责人: Hyunyoung Jeong
• 金额: $ 24.47万
• 依托单位: PURDUE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-09-01 至 2024-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10477476
• 关键词: Affect; Antibiotics; Antineoplastic Agents; Biological; Botanicals; Cecum; Chemicals; Clinical; Collection; Diet; Disease; Drug Compounding; Drug Exposure; Drug Interactions; Drug Prescriptions; Enterococcus faecalis; Enzymes; Etoposide; Eubacterium; Exposure to; Flavonoids; Fruit; Future; Goals; Health; Human; Incidence; Incubated; Individual; Knowledge; Lignans; Metabolism; Morbidity - disease rate; Mus; Non-Prescription Drugs; O-Demethylating Oxidoreductases; Oral; Organ; Outcome; Pathway interactions; Pharmaceutical Preparations; Pharmacotherapy; Phenols; Plants; Play; Prevalence; Research; Role; Small Intestines; Substrate Specificity; Testing; Xenobiotic Metabolism; Xenobiotics; adverse drug reaction; demethylation; dietary supplements; drug disposition; drug metabolism; genetic approach; gut bacteria; gut microbiota; insight; mortality; novel; prevent; response; stool sample

The gut microbiota has increasingly been recognized as a xenobiotic-metabolizing organ involved in drug bioactivation/inactivation and elimination. Changes in gut bacterial composition and/or the activity of gut bacterial drug-metabolizing enzymes may change systemic exposure to drugs and thus increase the incidence of adverse drug reactions. In this proposal, we aim to define a previously unappreciated gut bacterial O- demethylation as a potential drug-metabolizing pathway for compounds containing the methoxylated aromatic ring(s). Various botanical compounds undergo gut bacterial O-demethylation, but it was completely unknown whether drugs are also subject to gut bacterial O-demethylation. In our preliminary study, we showed that several gut bacteria known to O-demethylate botanical substrates catalyze the O-demethylation of an oral anticancer drug etoposide, producing a less active metabolite M1. Moreover, we have found that systemic exposure to orally administered etoposide is 2-fold higher in mice pre-treated with non-absorbable antibiotics, while M1 systemic exposure is 3-fold lower in the mice. These results indicate that gut bacterial O- demethylation contributes significantly to the pre-systemic elimination of etoposide. We also identified a new gut bacterium previously unknown for O-demethylation activity. Expanding our findings in preliminary studies, we aim to obtain the landscape of gut bacterial O-demethylation by testing ~70 drug compounds containing O- methylated aromatic rings for O-demethylation (Aim 1) and by identifying and characterizing gut bacterial O- demethylases (Aim 2). The proposed research will establish new paradigms in our understanding of xenobiotic metabolism by gut bacteria as well as drug interactions involving gut bacterial O-demethylation.

肠道微生物群越来越被认为是参与药物的异生物质代谢器官 生物活化/失活和消除。肠道细菌组成和/或肠道活性的变化 细菌药物代谢酶可能会改变药物的全身暴露，从而增加发病率 的药物不良反应。在本提案中，我们的目标是定义一种以前未被重视的肠道细菌 O- 去甲基化作为含有甲氧基化芳香族化合物的潜在药物代谢途径 戒指。多种植物化合物会经历肠道细菌 O-去甲基化，但人们对此完全未知 药物是否也会受到肠道细菌 O-去甲基化的影响。在我们的初步研究中，我们表明 几种已知能够 O-去甲基化植物底物的肠道细菌催化口腔中的 O-去甲基化 抗癌药物依托泊苷，产生活性较低的代谢物 M1。此外，我们还发现，系统性 在用不可吸收的抗生素预处理的小鼠中，口服依托泊苷的暴露量增加了 2 倍， 而小鼠中 M1 的全身暴露量降低了 3 倍。这些结果表明肠道细菌 O- 去甲基化对依托泊苷的系统前消除有显着贡献。我们还确定了一个新的 以前未知 O-去甲基化活性的肠道细菌。扩大我们在初步研究中的发现， 我们的目标是通过测试约 70 种含有 O- 的药物化合物来了解肠道细菌 O- 去甲基化的情况 甲基化芳环用于 O- 去甲基化（目标 1），并通过识别和表征肠道细菌 O- 去甲基酶（目标 2）。拟议的研究将为我们理解外源性物质建立新的范式 肠道细菌的代谢以及涉及肠道细菌 O-去甲基化的药物相互作用。