TY - JOUR T1 - Hepatic Flavin-Containing Monooxygenase 3 Enzyme Suppressed by Type 1 Allergy-Produced Nitric Oxide JF - Drug Metabolism and Disposition JO - Drug Metab Dispos SP - 1189 LP - 1196 DO - 10.1124/dmd.117.076570 VL - 45 IS - 11 AU - Tadatoshi Tanino AU - Toru Bando AU - Akira Komada AU - Yukie Nojiri AU - Yuna Okada AU - Yukari Ueda AU - Eiichi Sakurai Y1 - 2017/11/01 UR - http://dmd.aspetjournals.org/content/45/11/1189.abstract N2 - Flavin-containing monooxygenases (FMOs) are major mammalian non-cytochrome P450 oxidative enzymes. T helper 2 cell–activated allergic diseases produce excess levels of nitric oxide (NO) that modify the functions of proteins. However, it remains unclear whether allergy-induced NO affects the pharmacokinetics of drugs metabolized by FMOs. This study investigated alterations of hepatic microsomal FMO1 and FMO3 activities in type 1 allergic mice and further examined the interaction of FMO1 and FMO3 with allergy-induced NO. Imipramine (IMP; FMO1 substrate) N-oxidation activity was not altered in allergic mice with high serum NO and immunoglobulin E levels. At 7 days after primary sensitization (PS7) or secondary sensitization (SS7), benzydamine (BDZ; FMO1 and FMO3 substrate) N-oxygenation was significantly decreased to 70% of individual controls. The expression levels of FMO1 and FMO3 proteins were not significantly changed in the sensitized mice. Hepatic inducible NO synthase (iNOS) mRNA level increased 5-fold and 15-fold in PS7 and SS7 mice, respectively, and hepatic tumor necrosis factor-α levels were greatly enhanced. When a selective iNOS inhibitor was injected into allergic mice, serum NO levels and BDZ N-oxygenation activity returned to control levels. NO directly suppressed BDZ N-oxygenation, which was probably related to FMO3-dependent metabolism in comparison with IMP N-oxidation. In hepatic microsomes from PS7 and SS7 mice, the suppression of BDZ N-oxygenation was restored by ascorbate. Therefore, type 1 allergic mice had differentially suppressed FMO3-dependent BDZ N-oxygenation. The suppression of FMO3 metabolism related to reversible S-nitrosyl modifications of iNOS-derived NO. NO is expected to alter FMO3-metabolic capacity–limited drug pharmacokinetics in humans. ER -