Hepatic Flavin-Containing Monooxygenase 3 Enzyme Suppressed by Type 1 Allergy-Produced Nitric Oxide
| Autor: | Toru Bando, Yukie Nojiri, Akira Komada, Eiichi Sakurai, Yukari Ueda, Tadatoshi Tanino, Yuna Okada |
|---|---|
| Rok vydání: | 2017 |
| Předmět: |
Hypersensitivity
Immediate Male 0301 basic medicine Imipramine Necrosis Ovalbumin Nitric Oxide Synthase Type II Pharmaceutical Science Pharmacology Benzydamine Nitric Oxide Immunoglobulin E 030226 pharmacology & pharmacy Nitric oxide Mice 03 medical and health sciences chemistry.chemical_compound 0302 clinical medicine Pharmacokinetics medicine Animals Humans RNA Messenger Sensitization Mice Inbred ICR biology Tumor Necrosis Factor-alpha Chemistry Metabolism Monooxygenase Disease Models Animal 030104 developmental biology medicine.anatomical_structure Liver Biochemistry Microsomes Liver Oxygenases biology.protein Microsome Female medicine.symptom Oxidation-Reduction |
| Zdroj: | Drug Metabolism and Disposition. 45:1189-1196 |
| ISSN: | 1521-009X 0090-9556 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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