Stiftung Tierärztliche Hochschule Hannover (TiHo)

Gut microbial transformation of the dietary mutagen MeIQx may reduce exposure levels without altering intestinal transport

ORCID
0000-0003-3526-4586
Affiliation
Department of Health Sciences and Technology, ETH Zürich, Zürich, Switzerland.
Zhang, Jianbo;
ORCID
0000-0002-5652-5258
Affiliation
Institute for Food Toxicology, University of Veterinary Medicine Hannover, Hannover, Germany.
Empl, Michael;
Affiliation
Department of Health Sciences and Technology, ETH Zürich, Zürich, Switzerland.
Schneider, Mirjam;
Affiliation
Department of Physiology, University of Veterinary Medicine Hannover, Hannover, Germany.
Schröder, Bernd;
Affiliation
Eawag, Dübendorf, Switzerland; School of Architecture, Civil and Environmental Engineering, EPF Lausanne, Switzerland.
Stadnicka-Michalak, Julita;
GND
1173439455
ORCID
0000-0003-2871-3064
Affiliation
Department of Physiology, University of Veterinary Medicine Hannover, Hannover, Germany.
Breves, Gerhard;
GND
114280789
ORCID
0000-0003-4878-8610
Affiliation
Institute for Food Toxicology, University of Veterinary Medicine Hannover, Hannover, Germany. Electronic address: pablo.steinberg@mri.bund.de.
Steinberg, Pablo;
Affiliation
Department of Health Sciences and Technology, ETH Zürich, Zürich, Switzerland. Electronic address: sturlas@ethz.ch.
Sturla, Shana J

The mutagen and probable human carcinogen 2-amino-3,8-dimethylimidazo[4,5-f]quinoxaline (MeIQx) is metabolized in the colon to 9-hydroxyl-2,7-dimethyl-7,9,10,11-tetrahydropyrimido[2',1':2,3]imidazo[4,5-f]quinoxaline (MeIQx-M1) by conjugation with microbially generated acrolein. However, whether this microbiota-controlled process alters systemic exposure and hepatotoxicity of MeIQx remains unclear. The physiological relevance of this microbial transformation on the systemic exposure of MeIQx was investigated using an in vitro-in vivo extrapolation approach. To address whether microbial transformation influences intestinal transport of MeIQx, the intestinal uptake of MeIQx and its metabolite MeIQx-M1 was quantified using Ussing chambers mounted with different intestinal segments from male Fischer 344 rats. Up to 0.4% of both MeIQx and MeIQx-M1 were transported from the mucosal side to the serosal side of intestinal tissue within 90 min, suggesting that the intestinal uptake of both compounds is similar. With the uptake rates of both compounds, physiologically based pharmacokinetic (PBPK) modeling of the fate of MeIQx in the human body including microbial transformation of MeIQx was performed. Results indicate for the first time that high levels of microbe-derived acrolein would be required to significantly reduce systemic exposure of MeIQx in humans. Finally, neither MeIQx nor MeIQx-M1 were cytotoxic towards human liver HepaRG cells at dietary or higher concentrations of MeIQx. In summary, these findings suggest that gut microbial transformation of heterocyclic amines has the potential to influence systemic human exposure to some extent, but may require significant gut microbial production of acrolein and that further investigations are needed to understand physiological levels of acrolein and competing biotransformation pathways.

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