Flavin monooxygenase 3 (FMO3) polymorphism in a white population: allele frequencies, mutation linkage, and functional effects on clozapine and caffeine metabolism.
OBJECTIVE
The flavin-containing monooxygenase 3 (FMO3) has been shown to be genetically polymorphic. In vitro, the enzyme contributes to the N-oxidation of clozapine, caffeine, and several other drugs. We therefore wanted to analyze population frequencies and allelic linkage of FMO3 mutations and their functional effect on the metabolism of clozapine and caffeine.


METHODS
This study included 204 patients treated with clozapine for schizophrenia and 192 healthy volunteers receiving a 100 mg oral test dose of caffeine. FMO3 polymorphisms M66I, P153L, E158K, V257M, E305X, E308G, and R492W were analyzed by polymerase chain reaction (PCR) and restriction fragment length polymorphism (RFLP) analysis. Ratios of serum clozapine N-oxide over clozapine and of urine theobromine versus paraxanthine were used as in vivo indicators of FMO3 activity.


RESULTS
From the known FMO3 amino acid variants, only K158 (frequency 0.426), G308 (0.225), and M257 (0.069) were found; mutations I66, L153, X305, and W492 were not found in the 396 subjects. Linkage analysis revealed seven different alleles; the most frequent of these was the wild-type E158-V257-E308 (0.534), followed by K158-V257-G308 (0.199) and K158-V257-E308 (0.192). Subjects with these frequent variants of FMO3, however, did not differ in clozapine N-oxidation or caffeine oxidation compared with the wild-type.


CONCLUSIONS
There are several genetic polymorphisms for the FMO3 enzyme. The effects on the metabolism of caffeine or clozapine could not be shown, indicating that the mutations have only minor functional effects or that substrate affinity is too low to be clinically relevant.
Sachse
C
C
Institut für Klinische Pharmakologie, Universitätsklinikum Charité, Humboldt-Universität zu Berlin, Germany.
Ruschen
S
S
Dettling
M
M
Schley
J
J
Bauer
S
S
Müller-Oerlinghausen
B
B
Roots
I
I
Brockmöller
J
J
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000483:Alleles; D014150:Antipsychotic Agents / Q000493:pharmacokinetics*; D002110:Caffeine / Q000493:pharmacokinetics*; D016022:Case-Control Studies; D000697:Central Nervous System Stimulants / Q000493:pharmacokinetics*; D003024:Clozapine / Q000493:pharmacokinetics*; D017931:DNA Primers; D005260:Female; D008040:Genetic Linkage; D005838:Genotype; D006801:Humans; D008297:Male; D008875:Middle Aged; D009154:Mutation; D010105:Oxygenases / Q000235:genetics*; D016133:Polymerase Chain Reaction; D012150:Polymorphism, Restriction Fragment Length; D012559:Schizophrenia / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism*; D012702:Serotonin Antagonists / Q000493:pharmacokinetics*; D013997:Time Factors; D044465:White People / Q000235:genetics*
D014150:Antipsychotic Agents; D000697:Central Nervous System Stimulants; D017931:DNA Primers; D012702:Serotonin Antagonists; D002110:Caffeine; D010105:Oxygenases; C020066:dimethylaniline monooxygenase (N-oxide forming); D003024:Clozapine