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Metabolic Activation of Flavin Monooxygenase-mediated Trimethylamine-N-Oxide Formation in Experimental Kidney Disease
Alexander J Prokopienko1, Raymond E West1, Daniel P Schrum1
1Center for Clinical Pharmaceutical Sciences, Department of Pharmaceutical Sciences or Department of Pharmacy and Therapeutics, School of Pharmacy, University of Pittsburgh, Pittsburgh, PA, United States.
Insights
Cardiovascular disease (CVD) in chronic kidney disease (CKD) patients is linked to elevated Trimethylamine N-oxide (TMAO). Increased TMAO formation in CKD is driven by metabolic activation of flavin-containing monooxygenase (FMO), a potential therapeutic target.
Area of Science:
- Nephrology
- Cardiology
- Biochemistry
Background:
- Cardiovascular disease (CVD) is the primary cause of mortality in chronic kidney disease (CKD) patients.
- Traditional CVD risk factors do not fully explain this increased risk, indicating non-traditional factors like Trimethylamine N-oxide (TMAO) are involved.
- Elevated serum TMAO in CKD patients correlates with atherosclerosis and may stem from increased hepatic flavin-containing monooxygenase (FMO) activity.
Purpose of the Study:
- To investigate the underlying mechanisms responsible for the heightened FMO activity observed in chronic kidney disease (CKD).
- To determine if metabolic activation contributes to increased Trimethylamine N-oxide (TMAO) production in CKD.
Main Methods:
- In vitro experiments using liver microsomes from experimental chronic kidney disease (CKD) and control rats.
- Assessed flavin-containing monooxygenase (FMO) activity using trimethylamine as a probe substrate.
- Evaluated the effects of the FMO activator octylamine and human uremic serum on FMO activity and Trimethylamine N-oxide (TMAO) formation.
Main Results:
- Flavin-containing monooxygenase (FMO)-mediated Trimethylamine N-oxide (TMAO) formation was significantly higher in chronic kidney disease (CKD) rat models compared to controls.
- Neither FMO gene nor protein expression levels were altered between CKD and control groups.
- Metabolic activation, induced by octylamine and human uremic serum, markedly enhanced FMO-mediated TMAO production in CKD.
Conclusions:
- Metabolic activation of flavin-containing monooxygenase (FMO) represents a novel mechanism contributing to increased Trimethylamine N-oxide (TMAO) production in chronic kidney disease (CKD).
- This enhanced FMO activity and subsequent TMAO formation in CKD patients present a potential therapeutic target for reducing cardiovascular disease (CVD) risk.
Abstract:
Cardiovascular disease (CVD) remains the leading cause of death in chronic kidney disease (CKD) patients despite treatment of traditional risk factors, suggesting that non-traditional CVD risk factors are involved. Trimethylamine-N-oxide (TMAO) correlates with atherosclerosis burden in CKD patients and may be a non-traditional CVD risk factor. Serum TMAO concentrations are significantly increased in CKD patients, which may be due in part to increased hepatic flavin monooxygenase (FMO)-mediated TMAO formation. The objective of this work was to elucidate the mechanism of increased FMO activity in CKD. In this study, FMO enzyme activity experiments were conducted in vitro with liver microsomes isolated from experimental CKD and control rats. Trimethylamine was used as a probe substrate to assess FMO activity. The FMO activator octylamine and human uremic serum were evaluated. FMO gene and protein expression were also determined. FMO-mediated TMAO formation was increased in CKD versus control. Although gene and protein expression of FMO were not changed, metabolic activation elicited by octylamine and human uremic serum increased FMO-mediated TMAO formation. The findings suggest that metabolic activation of FMO-mediated TMAO formation is a novel mechanism that contributes to increased TMAO formation in CKD and represents a therapeutic target to reduce TMAO exposure and CVD.
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