A. Q. Zhang

Dietary Precursors of Trimethylamine in Man: A Pilot Study

An increased urinary excretion of trimethylamine and its N-oxide were observed in man following the oral intake (15 mmol) of choline (63% dose as trimethylamine and its N-oxide), D,L-carnitine (31% dose) and trimethylamine N-oxide (78% dose). Similar ingestion of betaine, creatinine or lecithin failed to elicit any significant increases. Of 46 different foods investigated, only fish and other sea-products gave rise to significant increases in urinary trimethylamine and N-oxide. Ingestion of fruits, vegetables, cereal and dairy produce, and meats had no measurable effects. Reasons for the apparent lack of trimethylamine provision by foods previously thought to be precursors are given and the role of gut microflora highlighted.

Determination of trimethylamine and related aliphatic amines in human urine by head-space gas chromatography

A rapid and simple assay procedure employing head-space gas chromatography has been developed for the routine quantification of volatile methylamines and stable trimethylamine N-oxide present in human urine. This assay will enable the rapid screening of patients and aid the diagnosis of fish odour syndrome.

Fish odour syndrome: Verification of carrier detection test

SummaryAn oral trimethylamine challenge test has been used to confirm the heterozygous status of patients with ‘fish-odour syndrome’. By measuring the percentage of total urinary trimethylamine-related material excreted as theN-oxide, no discrimination could be made between obligate heterozygotes (parents of ‘fish-odour syndrome’ patients) (n=15; 96±2%, range 92–98%) and control individuals (parents of unaffected children) (n=16; 96±2%, range 93–99%) on a normal diet. However, after ingesting a trimethylamine load (600 mg base) the obligate heterozygotes were clearly distinguishable (76±3%, range 71–79%) from controls (95±2%, range 91–99%) (t-test;p<0.001). One of a hundred apparently normal volunteers who were subsequently challenged with trimethylamine had anN-oxidation capacity which fell within the range found among the obligate heterozygotes.

Studies on the discontinuous N-oxidation of trimethylamine among Jordanian, Ecuadorian and New Guinean populations.

Whilst the majority of individuals within a British white population are able to convert greater than 90% of their dietary-derived trimethylamine to its N-oxide, outliers exist who show varying degrees of impairment. Such individuals excrete unoxidized trimethylamine in their urine and, if sufficiently compromised, may experience malodour problems (Fish-Odour Syndrome). Little information concerning this polymorphic N-oxidation process is available in other ethnic groups and the present study explores Jordanian, Ecuadorian and New Guinean populations. Subjects with a relative deficiency in N-oxidation were found in all three groups, with 1.7% (2/116) Jordanian, 3.8% (3/8) Ecuadorian and 11.0% (11/100) New Guinean excreting 80% or less of their total trimethylamine as the N-oxide. Two subjects from the Ecuadorian population (4% and 33% total trimethylamine as the N-oxide) exhibited frank trimethylaminuria. These observations suggest that a compromised ability to N-oxidize trimethylamine is detectable in several ethnic groups and that this polymorphic phenomenon may have a widespread existence.

Dimethylamine formation in man

Trimethylamine N-oxide, a common food component, has been identified as a major source of urinary dimethylamine in man. The potential pathophysiological consequences of exposure to dietary derived dimethylamine are raised.

Dimethylamine in human urine

The urinary excretion of dimethylamine has been measured in 203 unrelated healthy volunteers (102 male) who maintained their normal diets. The results for female volunteers are the first reported in the literature. The average daily output was 17.43 +/- 11.80 mg (mean +/- S.D.) (21.21 +/- 14.78 male; 13.74 +/- 5.65 female) with values for the majority of the population lying within the 0.68-35.72 mg range. Four male outliers excreted up to 109.2 mg; these large amounts of dimethylamine were presumed to be of dietary origin. The literature pertaining to urinary levels of dimethylamine has been summarised and integrated with the present observations.

Metabolic disposition of [14C]-trimethylamine N-oxide in rat: variation with dose and route of administration

1. Urine was the major route of excretion of radioactivity (95% dose in 0-24 h) following the oral, intravenous or intraperitoneal administration of [14C]-trimethylamine N-oxide dihydrate (1 mmol/kg body wt) to the adult male Wistar rat. A further 3-4% was voided in the urine during 24-72 h. Only fractional amounts were detected in the faeces, or were retained within tissues 3 days after administration. 2. Biliary secretion of radioactivity was insignificant (0.18% in 0-4 h) but larger amounts were secreted directly into the lumen of the gastrointestinal tract, especially the small intestine (2.6% in 0-1 h). 3. The only radioactive compounds identified in the urine were trimethylamine N-oxide and dimethylamine. Larger amounts of dimethylamine were excreted following oral administration (10%) as opposed to intravenous (2.5%) or intraperitoneal (1.5%) input. This production of dimethylamine occurred over a 100-fold oral trimethylamine N-oxide dose range (0.3-30 mmol/kg body wt). Incubation of trimethylamine N-oxide with gut contents (especially colon and rectum) led to the formation of dimethylamine.

Discontinuous distribution of N-oxidation of dietary-derived trimethylamine in a British population

1. Whilst the majority of individuals within a British white population are able to convert > 90% of their dietary-derived trimethylamine to its N-oxide, outliers exist who show varying degrees of decreased metabolism. Such individuals, excrete unoxidized trimethylamine in their urine and, if N-oxidation is sufficiently low, may experience malodour problems (Fish-Odour syndrome). 2. Such observations have now been extended to a much larger group (n = 421; 221 males) of British white volunteers recruited from staff and students of Imperial College Medical School at St. Marys, London. Each subject collected a 0-24-h urine sample, which was subsequently analysed for total trimethylamine and trimethylamine N-oxide content. 3. Sixteen subjects (3.8% population; seven male, nine female) excreted < 90% of their total trimethylamine output as N-oxide. All six subjects who excreted < 80% as N-oxide (indicative of potential heterozygous status for deficient N-oxidation-fish odour syndrome) were female.

Fate of dimethylamine in man

1. The fate of [14C]-dimethylamine was investigated following oral administration to four male volunteers. 2. The major route of excretion was urine, with 94% of the administered radioactivity being voided over 3 days (87% during the first 24 h). Small amounts (1-3%) of radioactivity were found in the faeces and expired air. 3. Metabolism was limited with only 5% being demethylated to methylamine. The remainder of the dose was excreted unchanged. 4. Pharmacokinetic studies indicated rapid (t1/2ab = 8 min) and extensive absorption (bioavailability = 82%) from the gastrointestinal tract followed by widespread distribution and a fairly prompt excretion (t1/2el = 6-7 h) with a plasma clearance of 190 ml/min.

Dimethylamine and diet.

Forty-six different foods eaten by six healthy male volunteers were investigated as potential sources of the aliphatic secondary amine, dimethylamine. None that were representatives from the fruit and vegetable, meat, dairy and grain produce categories afforded any measurable elevation in urinary dimethylamine output following ingestion. All of the statistically significant increases occurred after consumption of fish and seafoods. However, within this category a wide variation was observed. The highest values were obtained for coley, squid and whiting with cod, haddock, sardine, skate and swordfish also producing substantial increases. Freshwater trout, plaice and prawns gave no discernable effect. It seems that not all fish and seafoods may be treated equally with regards to human dimethylamine exposure and that the situation is more complicated than at first appears.