Gut bacterial O-demethylation

肠道微生物群越来越被认为是参与药物代谢的外源性代谢器官。 生物活化/灭活和消除。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 药物不良反应。在这项提议中，我们的目标是定义一种以前不受重视的肠道细菌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。各种植物化合物经历肠道细菌O-去甲基化，但这是完全未知的 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， 已知的几种使植物底物O-脱甲基化的肠道细菌催化口腔粘膜的O-脱甲基化， 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， 口服给药的依托泊苷暴露在用不可吸收的抗生素预处理的小鼠中高2倍， 而小鼠中M1的全身暴露量低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著贡献。我们还发现了一种新的 肠道细菌以前未知的O-去甲基化活性。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-的药物化合物来获得肠道细菌O-去甲基化的景观。 甲基化芳环用于O-去甲基化（Aim 1），并通过鉴定和表征肠道细菌O- 脱甲基酶（Aim 2）。这项研究将为我们理解生物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-脱甲基的药物相互作用。

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.