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Review
.2013 Mar;69(1):21-31.
doi: 10.1016/j.phrs.2012.07.009. Epub 2012 Aug 9.

Developing a metagenomic view of xenobiotic metabolism

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Review

Developing a metagenomic view of xenobiotic metabolism

Henry J Haiser et al. Pharmacol Res.2013 Mar.

Abstract

The microbes residing in and on the human body influence human physiology in many ways, particularly through their impact on the metabolism of xenobiotic compounds, including therapeutic drugs, antibiotics, and diet-derived bioactive compounds. Despite the importance of these interactions and the many possibilities for intervention, microbial xenobiotic metabolism remains a largely underexplored component of pharmacology. Here, we discuss the emerging evidence for both direct and indirect effects of the human gut microbiota on xenobiotic metabolism, and the initial links that have been made between specific compounds, diverse members of this complex community, and the microbial genes responsible. Furthermore, we highlight the many parallels to the now well-established field of environmental bioremediation, and the vast potential to leverage emerging metagenomic tools to shed new light on these important microbial biotransformations.

Copyright © 2012 Elsevier Ltd. All rights reserved.

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Conflict of interest statement

Conflict of interest

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1. Phylogenetic distribution of cultured gut isolates with enzymatic activities relevant to xenobiotic metabolism
Full-length aligned 16S rRNA gene sequences for bacteria of interest were retrieved from the Ribosomal Database Project website (Release 10, update 29) [99]. The “Tree Builder” tool was used withFusobacterium nucleatum as the outgroup. The resulting tree was exported in Newick format and annotated using the Interactive Tree of Life website [100]. Major bacterial phyla are shown in colored boxes: Actinobacteria (orange), Bacteroidetes (red), Firmicutes (blue), and Proteobacteria (yellow). Large circles indicate the presence of a confirmed enzymatic activity within each bacterial species. Nodes with a bootstrap value >70 are indicated by black squares.
Figure 2
Figure 2. Key examples of microbial biotransformations: (A) digoxin, (B) sulfasalazine, and (C) levodopa (L-DOPA)
Structures were obtained from the ChemBioDraw Ultra database (version 12.0.3.1216). The known organism or enzyme responsible is indicated for each transformation.
Figure 3
Figure 3. The complex host-microbial metabolism of irinotecan and phosphatidylcholine
(A) Irinotecan is administered intravenously in the inactive form (CPT-11), followed by activation and subsequent inactivation by host enzymes, and release into the gut via bile. Microbial enzymes can then reactivate these compounds; a process that can be blocked by orally administered inhibitors. (B) Phosphatidylcholine, consumed in many common foods or as a dietary supplement, is converted to choline followed by microbial production of TMA, the down-stream products of which can contribute to atheroschlerosis. Abbreviations: BG (microbial β-glucuronidase), CE (host carboxylesterases), CPT-11 (irinotecan), FMOs (hepatic flavin monooxygenases), PC (phosphatidylcholine), PLD (phospholipase D), TMA (trimethylamine), TMAO (trimethylamine oxide), and UGT (hepatic UDP-glucuronosyltransferases).
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