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Gut bacterial O-demethylation

肠道细菌O-去甲基化

基本信息

批准号：
10284189
负责人：
Hyunyoung Jeong
金额：
$ 19.38万
依托单位：
PURDUE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-09-01 至 2023-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10284189
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 Structure 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

项目摘要

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。