The human
flavin-containing monooxygenase (
FMO3) is a prominent
enzyme system that converts nucleophilic heteroatom-containing chemicals, drugs and
xenobiotics to more polar materials that are more efficiently excreted in the urine. The substrate specificity for FMO 3 is distinct from that of
FMO1. Human
FMO3 N-oxygenates primary, secondary and tertiary
amines whereas human
FMO1 is only highly efficient at N-oxygenating tertiary
amines. Both human
FMO1 and
FMO3 S-oxygenate a number of nucleophilic
sulfur-containing substrates and in some cases, does so with great stereoselectivity. Human
FMO3 is sensitive to steric features of the substrate and aliphatic
amines with linkages between the
nitrogen atom and a large aromatic group such as a
phenothiazine of at least five carbons are N-oxygenated significantly more efficiently than those substrates with two or three carbons. For
amines with smaller aromatic substituents such as
phenethylamines, often these compounds are efficiently N-oxygenated by human
FMO3. Currently, the most promising non-invasive probe of in vivo human
FMO3 functional activity is the formation of
trimethylamine N-oxide from
trimethylamine that comes from dietary
choline. (S)-
Nicotine N-1'-oxide formation can also be used as a highly stereoselective probe of human
FMO3 function for adult humans that
smoke cigarettes. Finally,
cimetidine S-oxygenation or
ranitidine N-oxidation can also be used as a functional probe of human
FMO3. With the recent observation of human
FMO3 genetic polymorphism and poor metabolism phenotype in certain human populations, variant human
FMO3 may contribute to
adverse drug reactions or exaggerated clinical response to certain medications. Knowledge of the substrate specificity for human
FMO3 may aid in the future design of more efficacious and less toxic drugs.