Gut bacterial O-demethylation

肠道微生物区系越来越被认为是与药物有关的异物代谢器官。 生物激活/失活和消除。肠道细菌组成和/或肠道活动的变化 细菌药物代谢酶可能改变全身药物暴露，从而增加发病率 药物不良反应。在这项提案中，我们的目标是定义一种以前未被认识的肠道细菌O- 脱甲基化作为含甲氧基芳香族化合物潜在的药物代谢途径 环(S)。各种植物化合物都会发生肠道细菌O-去甲基化，但这是完全未知的 药物是否也受到肠道细菌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，产生一种活性较低的代谢物M1。此外，我们发现系统性的 口服依托泊苷的小鼠在接受非吸收抗生素治疗前暴露于依托泊苷的几率是对照组的两倍， 而M1系统性暴露在小鼠身上的比例则低了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重要作用。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。在初步研究中扩大我们的发现， 我们的目标是通过测试~70个含有O-的药物化合物来获得肠道细菌O-去甲基化的图谱。 用于O-脱甲基化的甲基化芳环(目标1)以及通过鉴定和表征肠道细菌O- 去甲基酶(目标2)。这项拟议的研究将为我们理解异种生物建立新的范式。 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。

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.