Effect of Flavin-Containing Monooxygenase Genotype, Mouse Strain, and Gender on Trimethylamine N-oxide Production, Plasma Cholesterol Concentration, and an Index of Atherosclerosis

The objectives of the study were to determine the contribution, in mice, of members of the flavin-containing monooxygenase (FMO) family to the production of trimethylamine N-oxide (TMAO), a potential proatherogenic molecule, and whether, under normal dietary conditions, differences in TMAO production were associated with changes in plasma cholesterol concentration or with an index of atherosclerosis (Als). Concentrations of urinary trimethylamine (TMA) and TMAO and of plasma cholesterol were measured in 10-week-old male and female C57BL/6J and CD-1 mice and in mouse lines deficient in various Fmo genes (Fmo1(-/-), 2(-/-), 4(-/-) and Fmo5(-/-) ). In females most TMA N-oxygenation was catalyzed by FMO3, but in both genders 11-12% of TMA was converted to TMAO by FMO1. Gender-, Fmo genotype- and strain-related differences in TMAO production were accompanied by opposite effects on plasma cholesterol concentration. In all cases, plasma cholesterol was negatively correlated with TMAO production. Fmo genotype had no effect on Als. Als was positively correlated with TMAO in male C57BL/6J, Fmo1(-/-), 2(-/-), 4(-/-) and Fmo5(-/-) mice, but not in females, which produced substantially higher TMAO concentrations. The positive correlation in males was dependent on the inclusion of Fmo1(-/-), 2(-/-), 4(-/-) mice. In contrast, in male wild-type C57BL/6J and CD-1 mice Als was negatively correlated with TMAO. Thus, although a correlation between Als and TMAO was observed for a particular combination of mouse strain/gender/genotype this was not generally the case. Our results, therefore, indicate that under normal dietary conditions TMAO does not increase plasma cholesterol or act as a proatherogenic molecule