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Flavin monooxygenase 3 (FMO3) polymorphism in a white population: Allele frequencies, mutation linkage, and functional effects on clozapine and caffeine metabolism
Author(s) -
Sachse Christoph,
Ruschen Steffen,
Dettling Michael,
Schley Jörgen,
Bauer Steffen,
MöllerOerlinghausen Bruno,
Roots Ivar,
Brockmöller Jörgen
Publication year - 1999
Publication title -
clinical pharmacology and therapeutics
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.941
H-Index - 188
eISSN - 1532-6535
pISSN - 0009-9236
DOI - 10.1053/cp.1999.v66.a102203
Subject(s) - clozapine , population , genetics , paraxanthine , flavin containing monooxygenase , allele , allele frequency , caffeine , biology , chemistry , monooxygenase , biochemistry , enzyme , medicine , cytochrome p450 , endocrinology , gene , schizophrenia (object oriented programming) , cyp1a2 , environmental health , psychiatry
Aim 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 M 66 I, P 153 L, E 158 K, V 257 M, E 305 X, E 308 G, and R 492 W 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 K 158 (frequency 0.426), G 308 (0.225), and M 257 (0.069) were found; mutations I 66 , L 153 , X 305 , and W 492 were not found in the 396 subjects. Linkage analysis revealed seven different alleles; the most frequent of these was the wild‐type E 158 ‐V 257 ‐E 308 (0.534), followed by K 158 ‐V 257 ‐G 308 (0.199) and K 158 ‐V 257 ‐E 308 (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. Conclusion 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. Clinical Pharmacology & Therapeutics (1999) 66 , 431–438; doi: 10.1053/cp.1999.v66.a102203