# Gut bacterial O-demethylation

> **NIH NIH R21** · PURDUE UNIVERSITY · 2022 · $244,735

## Abstract

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.

## Key facts

- **NIH application ID:** 10477476
- **Project number:** 5R21AT011565-02
- **Recipient organization:** PURDUE UNIVERSITY
- **Principal Investigator:** Hyunyoung Jeong
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $244,735
- **Award type:** 5
- **Project period:** 2021-09-01 → 2024-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10477476

## Citation

> US National Institutes of Health, RePORTER application 10477476, Gut bacterial O-demethylation (5R21AT011565-02). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10477476. Licensed CC0.

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