RT Journal Article
SR Electronic
T1 Decreased Kidney Function is Associated with Enhanced Hepatic Flavin Monooxygenase Activity and Increased Circulating Trimethylamine N-oxide Concentrations in Mice
JF Drug Metabolism and Disposition
JO Drug Metab Dispos
FD American Society for Pharmacology and Experimental Therapeutics
SP dmd.118.081646
DO 10.1124/dmd.118.081646
A1 Cassandra Johnson
A1 Alexander J Prokopienko
A1 Raymond E West III
A1 Thomas D Nolin
A1 Jason R Stubbs
YR 2018
UL http://dmd.aspetjournals.org/content/early/2018/06/18/dmd.118.081646.abstract
AB Circulating trimethylamine N-oxide (TMAO) predicts poor cardiovascular outcomes in patients with chronic kidney disease (CKD). Accumulation of serum TMAO has been observed in CKD patients; however, the mechanisms contributing to this finding have been inadequately explored. The purpose of this study was to investigate the mechanisms responsible for TMAO accumulation in the setting of decreased kidney function using a CKD mouse model. Mice were fed a diet supplemented with 0.2% adenine to induce CKD, which resulted in increased serum TMAO concentrations (Females: CKD 29.4 ± 32.1 μM vs non-CKD 6.9 ± 6.1 μM, P<0.05; Males: CKD 18.5 ± 13.1 μM vs non-CKD 1.0 ± 0.5 μM, P<0.001). As anticipated, accumulation of circulating TMAO was accompanied by a decrease in renal clearance (Females: CKD 5.2 ± 3.8 L/min vs non-CKD 90.4 ± 78.1 L/min, P<0.01; Males: CKD 10.4 ± 8.1 L/min vs non-CKD 260.4 ± 134.5 L/min; P<0.001) and fractional excretion of TMAO. Additionally, CKD animals exhibited an increase in hepatic flavin monooxygenase (FMO)-mediated formation of TMAO (Females: CKD 125920 ± 2181 pmol/mg/60 min vs non-CKD 110299 ± 4196 pmol/mg/60 min, P<0.001; Males: CKD 131286 ± 2776 pmol/mg/60 min vs non-CKD 74269 ± 1558 pmol/mg/60 min, P<0.001), which likely resulted from increased FMO3 expression in CKD mice. The current study provides evidence that both decreased renal clearance and increased hepatic production of TMAO may contribute to increments in serum TMAO in the setting of CKD. Hepatic FMO activity may represent a novel therapeutic target for lowering circulating TMAO in CKD patients.