Gut bacterial O-demethylation

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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.