Riad Ayesh

A genetic polymorphism of the N-oxidation of trimethylamine in humans.

Trimethylamine (TMA) and its N‐oxide (TMAO) are normal components of human urine. They are present in the diet and also derived from the enterobacterial metabolism of precursors such as choline. Dietary TMA is almost entirely metabolized to and excreted as TMAO. However, the extent to which TMA undergoes N‐oxidation appears to be polymorphic in a British white population study (n = 169). Two propositi were identified with relative TMA N‐oxidation deficiency that was further confirmed by oral challenge with TMA (600 mg). The study of the families of the two propositi, as well as those of two identified subjects with trimethylaminuria, under both normal dietary conditions and after oral TMA challenge strongly indicates that the conditions of impaired N‐oxidation is inherited as a recessive trait. It is proposed that the N‐oxidation of TMA in humans is polymorphic and under single gene diallelic control in which individuals who are homozygous for the variant allele exhibit marked N‐oxidation deficiency and trimethylaminuria.

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.

Trimethylaminuria: The detection of carriers using a trimethylamine load test

SummaryA method potentially of value for investigating putative heterozygotes or carriers of trimethylaminuria by using a single oral dose of trimethylamine (TMA) is described. For healthy volunteers under normal dietary condition and following oral challenge with 300 mg and 600 mg TMA-base, over 90% of the urinary TMA was excreted in the form of TMA (93.6 ± 1.6%). However, at a dose level of 900 mg TMA-base, there was clear evidence of saturation of theN-oxidation reaction as urinary TMA excretion declined to 77.2% (range 74.8–78.9) of the total dose of TMA. By contrast, in pedigree studies based upon propositi with trimethylaminuria, several parents were identified who showed clear evidence of saturation of theN-oxidation of TMA at the 600 mg TMA-base dose level, but not at 300 mg TMA-base or under normal dietary condition. In these individuals, the proportion of urinary TMA as trimethylamineN-oxide (TMAO) declined to (77.3 ± 1.7%). Accordingly we propose that the oral administration of 600 mg TMA-base and the analysis of the following 0–8-h urine collection may be useful for the investigation of possible carriers of trimethylaminuria.

Disclosure of the metabolic retroversion of trimethylamine N‐oxide in humans: A pharmacogenetic approach

Trimethylamine N‐oxide (TMAO), which is naturally occurring in dietary marine fish, is well absorbed and excreted apparently unchanged as judged by end‐product analysis. Such observations may conceal the fact that the amine N‐oxide has undergone a sequence of deoxygenation and oxygenation reactions only to revert to the parental form and be excreted as such—a process that we propose to call metabolic retroversion. To evaluate this phenomenon for TMAO we have investigated the fate of the orally administered substance in healthy volunteers and in four subjects previously phenotyped as having an inherited deficiency with respect to the metabolic N‐oxidation of trimethylamine (TMA). Two of these subjects were typed as homozygous affected and the other two as “carriers.” If substantial reduction of orally administered TMAO occurs during the course of its postulated retroverted metabolism, it was hypothesized that this would be revealed by the extensive urinary excretion of unoxidized TMA by the four affected subjects. After oral TMAO administration in the four healthy subjects, >94% of the urinary TMA was in the form of TMAO and only <4% as the free base. However, after oral TMAO in the two homozygous‐affected subjects, unoxidized TMA accounted for 35% and 51%, respectively, of the total urinary TMA, the balance being due to TMAO. For the carrier subjects, TMA accounted for 12% and 16% of the total urinary TMA after TMAO administration. It is thus clear that the urinary excretion of unoxidized TMA is increased greatly in affected subjects with an inherited deficiency of N‐oxidation after the oral administration of TMAO. For the subjects investigated it appears that some 40% to 60% of an oral dose of TMAO undergoes reduction as part of the retroverted metabolic process. It is proposed that the use of human metabolic variants allows both a qualitative and quantitative assessment of retroverted metabolism as occurs with TMAO, and the principle may usefully be applied in other situations.

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.

Genetic polymorphism of trimethylamine N-oxidation

Example of a food idiosyncracy, known to represent a pharmacogenetic polymorphism: trimethylaminuria of «fish-odour syndrome». Primary trimethylaminuria must be distinguished from the trimethylaminurias which are non-genetic in origin and which are secondary to other factors such as renal or hepatic disease or overload with trimethylamine precursors

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.