title: Identification and Characterization of Trimethylamine-N-oxide Uptake and Efflux Transporters.
abstract: 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.
authors.affiliation: Department of Medicine, Division of Clinical Pharmacology, London Health Sciences Centre-University Hospital, Western University , 339 Windermere Road, London, Ontario N6A 5A5, Canada.
authors.forename: Wendy A
authors.initials: WA
authors.lastname: Teft
authors.affiliation: Department of Medicine, Division of Clinical Pharmacology, London Health Sciences Centre-University Hospital, Western University , 339 Windermere Road, London, Ontario N6A 5A5, Canada.
authors.forename: Bridget L
authors.initials: BL
authors.lastname: Morse
authors.affiliation: Department of Pediatrics, Division of Hematology and Oncology, Vanderbilt University School of Medicine , 338 PRB, 2220 Pierce Avenue, Nashville, Tennessee 37232-6310, United States.
authors.forename: Brenda F
authors.initials: BF
authors.lastname: Leake
authors.affiliation: Department of Medicine, Division of Clinical Pharmacology, London Health Sciences Centre-University Hospital, Western University , 339 Windermere Road, London, Ontario N6A 5A5, Canada.|Department of Medicine, Division of Gastroenterology, London Health Sciences Centre-University Hospital, Western University , 339 Windermere Road, London, Ontario N6A 5A5, Canada.
authors.forename: Aze
authors.initials: A
authors.lastname: Wilson
authors.affiliation: Department of Medicine, Division of Clinical Pharmacology, London Health Sciences Centre-University Hospital, Western University , 339 Windermere Road, London, Ontario N6A 5A5, Canada.
authors.forename: Sara E
authors.initials: SE
authors.lastname: Mansell
authors.affiliation: Department of Medicine and Robarts Research Institute, Schulich School of Medicine and Dentistry, Western University , London, Ontario N6A 5B7, Canada.
authors.forename: Robert A
authors.initials: RA
authors.lastname: Hegele
authors.affiliation: Department of Pediatrics, Division of Hematology and Oncology, Vanderbilt University School of Medicine , 338 PRB, 2220 Pierce Avenue, Nashville, Tennessee 37232-6310, United States.
authors.forename: Richard H
authors.initials: RH
authors.lastname: Ho
authors.affiliation: Department of Medicine, Division of Clinical Pharmacology, London Health Sciences Centre-University Hospital, Western University , 339 Windermere Road, London, Ontario N6A 5A5, Canada.|Department of Oncology, London Health Sciences Centre-Victoria Hospital, 800 Commissioners Road East, PO Box 5010, Western University , London, Ontario N6A 5W9, Canada.|Department of Physiology and Pharmacology, Medical Sciences Building, Western University , London, Ontario N6A 5C1, Canada.
authors.forename: Richard B
authors.identifier: 0000-0001-8148-1632
authors.initials: RB
authors.lastname: Kim
mesh_terms: D018528:ATP-Binding Cassette Transporters / Q000378:metabolism; D000818:Animals; D001692:Biological Transport; D002331:Carnitine / Q000378:metabolism; D006801:Humans; D008297:Male; D026901:Membrane Transport Proteins / Q000378:metabolism*; D008744:Methylamines / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D027701:Organic Cation Transport Proteins / Q000378:metabolism; D010087:Oxides / Q000378:metabolism*; D010105:Oxygenases / Q000378:metabolism
chemical_list: D018528:ATP-Binding Cassette Transporters; D026901:Membrane Transport Proteins; D008744:Methylamines; D027701:Organic Cation Transport Proteins; D010087:Oxides; D010105:Oxygenases; C020066:dimethylaniline monooxygenase (N-oxide forming); C023336:trimethylamine; D002331:Carnitine
keywords: BCRP; OCT2; TMAO; transporters