Dietary phenolics and their microbial metabolites are poor inhibitors of trimethylamine oxidation to trimethylamine N-oxide by hepatic flavin monooxygenase 3

Aug 7, 2023The Journal of nutritional biochemistry

Dietary plant compounds and their gut breakdown products only weakly block liver conversion of trimethylamine to trimethylamine N-oxide

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Abstract

High levels of trimethylamine N-oxide (TMAO) are associated with cardiovascular disease risk.

TMAO is produced from dietary choline through gut microbiota and host liver processes.
Specific gut bacteria convert choline to trimethylamine (TMA), which is then oxidized to TMAO by the FMO3 enzyme in the liver.
Chlorogenic acid and its metabolites were tested for their ability to inhibit the production of TMAO from TMA.
HepG2 cells lack the FMO3 enzyme necessary for TMAO production, while Hepa-1 cells express FMO3 but do not show enzymatic activity.
Rat hepatic microsomes demonstrated active FMO3, with optimal conditions for TMAO production identified.
Chlorogenic acid metabolites did not inhibit FMO3 activity at physiological or higher doses, suggesting their primary function may be related to inhibiting TMA production or absorption in the intestine.

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High circulating levels of trimethylamine N-oxide (TMAO) have been associated with cardiovascular disease risk. TMAO is formed through a microbiome-host pathway utilizing primarily dietary choline as a substrate. Specific gut microbiota transform choline into trimethylamine (TMA), and, when absorbed, host hepatic flavin-containing monooxygenase 3 (FMO3) oxidizes TMA into TMAO. Chlorogenic acid and its metabolites reduce microbial TMA production in vitro. However, little is known regarding the potential for chlorogenic acid and its bioavailable metabolites to inhibit the last step: hepatic conversion of TMA to TMAO. We developed a screening methodology to study FMO3-catalyzed production of TMAO from TMA. HepG2 cells were unable to oxidize TMA into TMAO due to their lack of FMO3 expression. Although Hepa-1 cells did express FMO3 when pretreated with TMA and NADPH, they lacked enzymatic activity to produce TMAO. Rat hepatic microsomes contained active FMO3. Optimal reaction conditions were: 50 µM TMA, 0.2 mM NADPH, and 33 µL microsomes/mL reaction. Methimazole (a known FMO3 competitive substrate) at 200 µM effectively reduced FMO3-catalyzed conversion of TMA to TMAO. However, bioavailable chlorogenic acid metabolites did not generally inhibit FMO3 at physiological (1 µM) nor supra-physiological (50 µM) doses. Thus, the effects of chlorogenic acid in regulating TMAO levels in vivo are unlikely to occur through direct FMO3 enzyme inhibition. Potential effects on FMO3 expression remain unknown. Intestinal inhibition of TMA production and/or absorption are thus likely their primary mechanisms of action.

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Dietary phenolics and their microbial metabolites are poor inhibitors of trimethylamine oxidation to trimethylamine N-oxide by hepatic flavin monooxygenase 3

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