Trimethylamine: Metabolic, Pharmacokinetic and Safety Aspects

Bain, Marcus A.; Fornasini, Gianfranco; Evans, Allan M.

doi:10.2174/1389200054021807

Cited by 85 publications

(73 citation statements)

References 140 publications

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“…Four 10-mL cultures of each media type (LS, CS, and C) were grown side by side at 37°C until reaching stationary phase (∼48 h). The concentration of d 9 -TMA in culture media and blanks was determined using LC-MS as described in SI Materials and Methods, except that the derivatization reaction contained 100 μL of 22 μM aqueous TMA solution for the C10(pB6) mutant samples and 100 μL of 2.2 mM aqueous TMA solution for the wild-type samples. The quenched derivatization reactions for the C10(pB6) mutant were analyzed without dilution, whereas for the wild-type samples, a 10-μL aliquot was diluted 100-fold before analysis.…”

Section: Methodsmentioning

confidence: 99%

“…This chemical transformation plays a significant role in many biological systems and impacts both the environment and human health. It has long been recognized that symbiotic gut microbes in humans (9)(10)(11) and other vertebrates (12)(13)(14) generate TMA from choline and that this metabolic activity is exclusively microbial. In humans, TMA is further processed to TMAO by the liver enzyme flavin-dependent monooxygenase 3 (FMO3) (15).…”

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confidence: 99%

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Microbial conversion of choline to trimethylamine requires a glycyl radical enzyme

Craciun

Balskus

2012

Proc. Natl. Acad. Sci. U.S.A.

561

578

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Choline and trimethylamine (TMA) are small molecules that play central roles in biological processes throughout all kingdoms of life. These ubiquitous metabolites are linked through a single biochemical transformation, the conversion of choline to TMA by anaerobic microorganisms. This metabolic activity, which contributes to methanogenesis and human disease, has been known for over a century but has eluded genetic and biochemical characterization. We have identified a gene cluster responsible for anaerobic choline degradation within the genome of a sulfate-reducing bacterium and verified its function using both a genetic knockout strategy and heterologous expression in Escherichia coli. Bioinformatics and electron paramagnetic resonance (EPR) spectroscopy revealed the involvement of a C-N bond cleaving glycyl radical enzyme in TMA production, which is unprecedented chemistry for this enzyme family. Our discovery provides the predictive capabilities needed to identify choline utilization clusters in numerous bacterial genomes, underscoring the importance and prevalence of this metabolic activity within the human microbiota and the environment.fragmentation | choline trimethylamine-lyase | gastrointestinal tract | metabolism | trimethylaminuria

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Section: Methodsmentioning

confidence: 99%

mentioning

confidence: 99%

Microbial conversion of choline to trimethylamine requires a glycyl radical enzyme

Craciun

Balskus

2012

Proc. Natl. Acad. Sci. U.S.A.

561

578

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“…Altered dietary exposure may potentially affect TMAO production by either reduction in the direct precursor substrate for TMA production or by altering gut microbial community composition, reducing the synthetic capacity to produce TMA from the different TMA-containing nutrients. TMA has long been recognized as an odorous byproduct of choline, PC, and L-carnitine during the decomposition of plants and animals, often by enterobacteria (31). Choline (free and esterified forms) and L-carnitine are the most common dietary nutrients ingested that produce TMA and TMAO (30,(37)(38)(39)55).…”

Section: R E V I E W S E R I E S : G U T M I C R O B I O M Ementioning

confidence: 99%

The contributory role of gut microbiota in cardiovascular disease

2014

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R e v i e w s e R i e s : g u t m i c R o b i o m eSeries Editor: Martin J. Blaser IntroductionCardiovascular disease (CVD) remains the leading cause of death in both the United States and industrialized societies, with growing incidence in developing countries (1). Factors contributing to CVD arise from genetic sources, environmental sources, or a combination of genetic and environmental sources (2). Despite extensive investigations in search of causal genetic variants, such as large-scale GWAS, less than one-fifth of attributable cardiovascular risk has been accounted for from genetic determinants (3, 4). At the same time, major advances in the treatment of atherosclerosis beyond high-potency lipid-lowering agents has not yet materialized (5). Indeed, even with high-potency statin therapy, at least a 50% residual risk remains (6), with the majority of events unchecked. Therefore, there is still ample room for improving our understanding of the processes contributing to CVD pathogenesis, and for improved prevention and treatment of CVD. While the recognizable contribution of genetics to CVD will no doubt significantly increase with time, a reassessment of environmental contributions to CVD pathogenesis and risks for adverse events is certainly worthwhile.Our largest environmental exposure is what we eat. Technically speaking, food is a foreign object that we take into our bodies in kilogram quantities every day. From the latest National Health and Nutrition Examination Survey (NHANES, 2009(NHANES, -2010, the majority of individuals sampled achieved an intermediate or poor Healthy Eating Index (1). However, dietary composition is often difficult to assess, and even precise quantification of dietary intake may not necessarily reveal the many known and unknown factors that may influence the contributions of specific dietary nutrients to disease susceptibility (7). There has also been an overwhelming lack of appreciation at the bedside regarding the intricate and complicated processes that transform ingested food into the myriad metabolites that enter the circulation and fulfill or adversely affect various functional and metabolic processes in the body.Over the past decade we have increasingly begun to appreciate the ecological diversity of microbes living symbiotically within us, a large proportion of which reside within our intestines. We now know that the human gut harbors more than 100 trillion microbial cells, far outnumbering the human host cells of the body (8). Indeed, a sobering fact is that Homo sapiens DNA is estimated to represent less than 10% of the total DNA within our bodies, due to the staggeringly large numbers of microbes that reside in and on us, primarily within our gut (9). Our microbial symbiont guests have coevolved with us and affect a wide range of physiologic and metabolic processes of the body. The major taxa present in gut microbiota consist primarily of 2 major bacterial phyla, Firmicutes and Bacteroidetes, whose proportions appear to remain remarkably stable over time within individu...

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“…Hypothetically, L-carnitine could be carcinogenic since it can be metabolized into trimethylamine and trimethylamine-N-oxide, both of which can be further metabolized into the potential carcinogenic compound N-nitrosodimethylamine (Bain et al 2005). However, at this moment there is no evidence that L-carnitine might indeed be carcinogenic in vivo in doses used in this study.…”

Section: Discussionmentioning

confidence: 69%

Carnitine Profile and Effect of Suppletion in Children with Renal Fanconi Syndrome due to Cystinosis

et al. 2014

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Background: Cystinosis is an autosomal recessive disorder marked by intralysosomal cystine accumulation. Patients present with generalized proximal tubular dysfunction called renal Fanconi syndrome. Urinary carnitine loss results in plasma and muscle carnitine deficiency, but no clinical signs of carnitine deficiency have been described. Also, the optimal dose of carnitine supplementation is undefined. This study aimed to determine whether currently recommended carnitine doses result in adequate correction of plasma carnitine.Methods: Five cystinosis patients with renal Fanconi syndrome, aged 2-18 years, were included. L-carnitine was prescribed 50 mg/kg/day since diagnosis: median 36 (range 18-207) months. Total and free plasma and urine carnitine and carnitine profiles were measured at study onset, after stopping L-carnitine for 3 months and 3 months after reintroducing L-carnitine 50 mg/kg/day.Results: At study onset, plasma free carnitine was normal in all patients, total carnitine (1/5), acetylcarnitine (3/5), and several short-and medium-chain acylcarnitines 10 carbons (5/5) were increased indicating carnitine over-supplementation. Three months after cessation, carnitine profiles normalized and 3/5 patients showed plasma carnitine deficiency. Three months after reintroduction, plasma free carnitine normalized in all patients, however, carnitine profiles were disturbed in 4/5 patients. Urine free carnitine, acetylcarnitine, and acylcarnitines 10 carbons were increased in all patients independent of carnitine supplementation.Conclusion: Administration of recommended doses L-carnitine (50 mg/kg/day) resulted in over-supplementation. Although the drug is considered to be rather safe, long-term effects of over-supplementation remain unknown warranting cautious use of high doses. Plasma carnitine profile might be used as a monitor, to prevent overdosing.

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Trimethylamine: Metabolic, Pharmacokinetic and Safety Aspects

Cited by 85 publications

References 140 publications

Microbial conversion of choline to trimethylamine requires a glycyl radical enzyme

Microbial conversion of choline to trimethylamine requires a glycyl radical enzyme

The contributory role of gut microbiota in cardiovascular disease

Carnitine Profile and Effect of Suppletion in Children with Renal Fanconi Syndrome due to Cystinosis

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