Trimethylamine metabolism

Marks R, Dudley F, Wan A (1978) Trimethylamine metabolism in liver disease. Lancet 20 1106-1107... 

Colby, J., and Zatman, L. J., 1973, Trimethylamine metabolism in obligate and facultative methylotrophs, Biochem. J. 132 1019112. 

King GM (1984) Metabolism of trimethylamine, choline and glycine betaine by sulfate-reducing and metha-nogenic bacteria in marine sediments. Appl Environ Microbiol 48 719-725. 

Metabolism of trimethylamine oxide in fish muscle involves an enzyme-catalyzed oxidation-reduction reaction. The enzyme responsible for the conversion of trimethylamine oxide to trimethylamine is known as trimethylamine-W-oxide reductase. This enzyme acts on nicotinamide adenine dinucleotide (NADH) and TMAO to produce NAD+, trimethylamine and water (Fig. 13.13.1). TMAO acts as the oxidizing agent and is reduced, while NADH undergoes oxidation as the reducing agent. 

Wolrath, H., Stahlbom, B., Hallen, A. and Forsum, U. (2005) Trimethylamine and trimethylamine oxide levels in normal women and women with bacterial vaginosis reflect a local metabolism in vaginal secretion as compared to urine. APMIS 113, 513-516. 

A1-Waiz M, Ayesh R, Mitchell SC, Idle JR, Smith RL (1989) Trimethylaminuria the detection of carriers using a trimethylamine load test. J Inherit Metab Dis 12 80-85 Al-Waiz M, Mitchell SC, Idle JR, Smith RL (1987) The relative importance of N-oxidation and N-demethylation in the metabolism of trimethylamine in man. Toxicology 43 117-121 Anonymous (1980) Workplace environmental exposure level guide. Trimethylamine. Am Ind Hyg Assoc J 41 A35-A37... 

There is also a genetic deficiency in FM03 in humans leading to Fish Odor syndrome, which results from the inability of the afflicted individuals to metabolism trimethylamine, which has a strong fishy smell, to the N-oxide, which has no smell. 

Tertiary amines such as trimethylamine and dimethylamine had long been known to be metabolized to A -oxides by a microsomal amine oxidase that was not dependent on CYP. This enzyme, now known as the microsomal flavin-containing monooxygenase (FMO), is also dependent on NADPH and 02, and has been purified to homogeneity from a number of species. Isolation and characterization of the enzyme from liver and lung samples provided evidence of clearly distinct physicochemical properties and substrate specificities suggesting the presence of at least two different isoforms. Subsequent studies have verified the presence of multiple forms of the enzyme. 

A nitrogen-containing compound, trimethylamine, is produced in a complaint called fish odour syndrome , where the sweat, breath and urine all smell of rotting fish. It is caused by a metabolic liver malfunction and releases trimethylamine in the bowel and gut. Drugs and dietary control can cure the condition. 

The total body content of carnitine is about 100 mmol, and about 5% of this turns over daily. Plasma total carnitine is between 36 to 83 /rmol per L in men and 28 to 75 /rmol per L in women, mainly as free carnitine. Although both free carnitine and acyl carnitine esters are excreted in the urine, much is oxidized to trimethylamine and trimethylamine oxide. It is not known whether the formation of trimethylamine and trimethylamine oxide is caused by endogenous enzymes or intestinal bacterial metabolism of carnitine. 

About 30% of dietary phosphatidylcholine is absorbed intact into the lymphatic system the remainder is hydrolyzed to lysolecithin in the intestinal mucosa and to free choline in the liver. Free choline in the diet is largely metabolized by intestinal bacteria, forming trimethylamine, which is absorbed and excreted in the urine. Only about 30% of free choline is absorbed intact. 

Nicotine is an example of a compound that undergoes FM03-catalyzed N-oxidation, as shown in Scheme 11.27. About 4% of nicotine is stereoselec-tively metabolized to trans-(S)-(—)-nicotine N-V oxide in humans by FM03, whereas 30% of an administered dose appears as cotinine, a CYP2A6 product (34, 35). Other examples of FMO N-oxidation include trimethylamine, amphetamine, and the phenothi-azines (33). As described previously, FM03 catalyzes S-oxidation of substrates such as cimetidine, shown in Scheme 11.28, and chlorpromazine, also a CYP3A substrate (Scheme 11.22). 

Choline is metabolized to trimethylamine, which is excreted in skin, lungs, and kidney. 

---