Open AccessIdentification and Characterization of Trimethylamine-N-oxide Uptake and Efflux Transporters
Author(s) -
Wendy A. Teft,
Bridget L. Morse,
Brenda F. Leake,
Aze Wilson,
Sara E. Mansell,
Robert A. Hegele,
Richard Ho,
Richard B. Kim
Publication year - 2016
Publication title -
molecular pharmaceutics
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.13
H-Index - 127
eISSN - 1543-8392
pISSN - 1543-8384
DOI - 10.1021/acs.molpharmaceut.6b00937
Subject(s) - trimethylamine n oxide , efflux , organic cation transport proteins , chemistry , transporter , organic anion transporter 1 , atp binding cassette transporter , abcg2 , in vivo , flavin containing monooxygenase , choline , carnitine , biochemistry , pharmacology , biology , monooxygenase , trimethylamine , metabolism , cytochrome p450 , gene , genetics
Trimethylamine-N-oxide (TMAO) is a recently identified predictor of cardiovascular and chronic kidney disease. TMAO is primarily generated through gut-microbiome mediated conversion of dietary choline and carnitine to TMA, which is converted to TMAO by hepatic flavin monooxygenase 3 (FMO3) and subsequently undergoes renal elimination. We investigated the role of uptake and efflux drug transporters in TMAO disposition in vitro and in vivo. After screening a large array of uptake transporters, we show organic cation transporter 2 (OCT2) is the key transporter for TMAO cellular uptake. In Oct1/2 knockout mice, we observed increased plasma TMAO levels with reduced renal retention, suggesting the importance of Oct2 in facilitating the uptake of TMAO into renal tubular cells in vivo. Multiple transporters of the ATP-binding cassette (ABC) family, including ABCG2 (BCRP) and ABCB1 (MDR1), were capable of TMAO efflux. In human subjects, clinical, dietary, and pharmacogenetic covariates were evaluated for contribution to TMAO levels in a cohort of dyslipidemic patients (n = 405). Interestingly, genetic variation in ABCG2, but not other transporters, appeared to play a role in modulating TMAO exposure.