title: Potential for drug interactions mediated by polymorphic flavin-containing monooxygenase 3 in human livers.
abstract: Human flavin-containing monooxygenase 3 (FMO3) in the liver catalyzes a variety of oxygenations of nitrogen- and sulfur-containing medicines and xenobiotic substances. Because of growing interest in drug interactions mediated by polymorphic FMO3, benzydamine N-oxygenation by human FMO3 was investigated as a model reaction. Among the 41 compounds tested, trimethylamine, methimazole, itopride, and tozasertib (50 μM) suppressed benzydamine N-oxygenation at a substrate concentration of 50 μM by approximately 50% after co-incubation. Suppression of N-oxygenation of benzydamine, trimethylamine, itopride, and tozasertib and S-oxygenation of methimazole and sulindac sulfide after co-incubation with the other five of these six substrates was compared using FMO3 proteins recombinantly expressed in bacterial membranes. Apparent competitive inhibition by methimazole (0-50 μM) of sulindac sulfide S-oxygenation was observed with FMO3 proteins. Sulindac sulfide S-oxygenation activity of Arg205Cys variant FMO3 protein was likely to be suppressed more by methimazole than wild-type or Val257Met variant FMO3 protein was. These results suggest that genetic polymorphism in the human FMO3 gene may lead to changes of drug interactions for N- or S-oxygenations of xenobiotics and endogenous substances and that a probe battery system of benzydamine N-oxygenation and sulindac sulfide S-oxygenation activities is recommended to clarify the drug interactions mediated by FMO3.
authors.affiliation: Laboratory of DMPK, Showa Pharmaceutical University, 3-3165 Higashi-tamagawa Gakuen, Machida, Tokyo 194-8543, Japan.
authors.forename: Makiko
authors.initials: M
authors.lastname: Shimizu
authors.affiliation: Laboratory of DMPK, Showa Pharmaceutical University, 3-3165 Higashi-tamagawa Gakuen, Machida, Tokyo 194-8543, Japan.
authors.forename: Arisa
authors.initials: A
authors.lastname: Shiraishi
authors.affiliation: Laboratory of DMPK, Showa Pharmaceutical University, 3-3165 Higashi-tamagawa Gakuen, Machida, Tokyo 194-8543, Japan.
authors.forename: Ayumi
authors.initials: A
authors.lastname: Sato
authors.affiliation: Laboratory of DMPK, Showa Pharmaceutical University, 3-3165 Higashi-tamagawa Gakuen, Machida, Tokyo 194-8543, Japan.
authors.forename: Satomi
authors.initials: S
authors.lastname: Nagashima
authors.affiliation: Laboratory of DMPK, Showa Pharmaceutical University, 3-3165 Higashi-tamagawa Gakuen, Machida, Tokyo 194-8543, Japan. Electronic address: hyamazak@ac.shoyaku.ac.jp.
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Yamazaki
mesh_terms: D001591:Benzydamine / Q000737:chemistry / Q000378:metabolism*; D002384:Catalysis; D004347:Drug Interactions; D006801:Humans; D066298:In Vitro Techniques; D008862:Microsomes, Liver / Q000201:enzymology / Q000378:metabolism*; D010105:Oxygenases / Q000235:genetics* / Q000378:metabolism*; D004364:Pharmaceutical Preparations / Q000737:chemistry / Q000378:metabolism*; D011110:Polymorphism, Genetic; D011994:Recombinant Proteins; D013379:Substrate Specificity
chemical_list: D004364:Pharmaceutical Preparations; D011994:Recombinant Proteins; D001591:Benzydamine; D010105:Oxygenases; C020066:dimethylaniline monooxygenase (N-oxide forming)
keywords: Drug interaction; Drug oxygenation; FMO3; FMO3 activity; FMO3 polymorphism