Identification and Characterization of Trimethylamine-N-oxide Uptake and Efflux Transporters

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• 作者：Wendy A. Teft ; Bridget L. Morse ; Brenda F. Leake ; Aze Wilson ; Sara E. Mansell ; Robert A. Hegele ; Richard H. Ho ; Richard B. Kim
• 刊名：Molecular Pharmaceutics
• 出版年：2017
• 出版时间：January 3, 2017
• 年：2017
• 卷：14
• 期：1
• 页码：310-318
• 全文大小：388K
• ISSN：1543-8392

文摘

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.