In vivo variability of TMA oxidation is partially mediated by polymorphisms of the FMO3 gene

Trimethylaminuria (TMAU) results from an accumulation of an excessive amoun t of unoxidized trimethylamine that is excreted in urine and body secretion s. Mutations of the flavin-containing monooxygenase 3 (FMO3) gene (a hepati c phase I drug-metabolizing enzyme) account for the severe recessively enco ded form of this condition. We have previously described a number of FMO3 p olymorphisms which in vitro exhibit reduced substrate affinity for several FMO substrates. Here we show that three prevalent polymorphisms (E158K, V25 7M, and E308G) inherited in particular combinations confer a slight decreas e in TMA oxidation under normal physiological conditions, which may be clin ically "silent." With the use of substrate loading or with the interaction of other known modulators of FMO3 activity such as hormonal influences, the se genotypes may predispose to mild TMAU. (C) 2001 Academic Press.