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Flavin‐Containing Monooxygenase 3 Polymorphic Variants Significantly Affect Clearance of Tamoxifen and Clomiphene
Author(s) -
Catucci Gianluca,
Bortolussi Stefania,
Rampolla Giulia,
Cusumano Debora,
Gilardi Gianfranco,
Sadeghi Sheila J.
Publication year - 2018
Publication title -
basic and clinical pharmacology and toxicology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.805
H-Index - 90
eISSN - 1742-7843
pISSN - 1742-7835
DOI - 10.1111/bcpt.13089
Subject(s) - single nucleotide polymorphism , flavin containing monooxygenase , drug metabolism , monooxygenase , tamoxifen , enzyme , pharmacology , biology , metabolism , drug , chemistry , genotype , biochemistry , genetics , cancer , cytochrome p450 , breast cancer , gene
Human flavin‐containing monooxygenase 3 ( hFMO 3) is a drug‐metabolising enzyme that oxygenates many drugs and xenobiotics in the liver. This enzyme is also known to exhibit single nucleotide polymorphisms ( SNP s) that can alter the rates of monooxygenation of therapeutic agents. The purpose of this study was to investigate the effect of the three common polymorphic variants of hFMO 3 (V257M, E158K and E308G) on the metabolism and clearance of three structurally similar compounds: tamoxifen (breast cancer medication), clomiphene (infertility medication) and GSK 5182 (antidiabetic lead molecule). For GSK 5182, none of the three variants showed any significant differences in its metabolism when compared to the wild‐type enzyme. In the case of clomiphene, two of the variants, V257M and E308G, exhibited a significant increase in all the kinetic parameters measured with nearly two times faster clearance. Finally, for tamoxifen, a mixed behaviour was observed; E158K variant showed a significantly higher clearance compared to the wild type, whereas V257M mutation had the opposite effect. Overall, the data obtained demonstrate that there is no direct correlation between the SNP s and the metabolism of these three hFMO 3 substrates. The metabolic capacity is both variant‐dependent and substrate‐dependent and therefore when testing new drugs or administering already approved therapies, these differences should be taken into consideration.