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. Clinical Pharmacology and Therapeutics (1987) 42, 608–612; doi:10.1038/clpt.1987.207