Potential for drug interactions mediated by polymorphic flavin-containing monooxygenase 3 in human livers

Drug Metabolism and Pharmacokinetics
Makiko ShimizuHiroshi Yamazaki

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-oxy...Continue Reading

References

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Citations

Jun 15, 2016·Drug Metabolism and Disposition : the Biological Fate of Chemicals·Robert S Foti, Deepak K Dalvie
Aug 10, 2016·Archives of Biochemistry and Biophysics·Heba AbdelwahabPablo Sobrado
Oct 6, 2016·PloS One·Heba AbdelwahabPablo Sobrado
Feb 2, 2017·Xenobiotica; the Fate of Foreign Compounds in Biological Systems·Miho Yamazaki-NishiokaHiroshi Yamazaki
Sep 30, 2016·Expert Opinion on Drug Metabolism & Toxicology·Ian R Phillips, Elizabeth A Shephard
Oct 24, 2018·Xenobiotica; the Fate of Foreign Compounds in Biological Systems·Makiko ShimizuHiroshi Yamazaki
Aug 2, 2017·Drug Metabolism and Disposition : the Biological Fate of Chemicals·Tadatoshi TaninoEiichi Sakurai
Mar 5, 2017·Drug Metabolism and Disposition : the Biological Fate of Chemicals·Shotaro UeharaHiroshi Yamazaki
Jul 19, 2019·Xenobiotica; the Fate of Foreign Compounds in Biological Systems·Ian R Phillips, Elizabeth A Shephard
Aug 14, 2019·Microbial Cell Factories·Chongliang Gao, Tingjie Zheng

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