Deletion of the mouse Fmo1 gene results in enhanced pharmacological behavioural responses to imipramine.

摘要: Objectives Many drugs are the subject of multipathway oxidative metabolism catalyzed by one or more cytochromes P450 flavin-containing monooxygenases (FMOs). This complicates assessment role individual enzymes in metabolizing drug and, hence, understanding its pharmacogenetics. To define FMOs metabolism, we produced FMO-deficient mice.Methods An Fmo1(-/-), Fmo2(-/-), Fmo4(-/-) mouse line was using chromosomal engineering and Cre-IoxP technology. assess utility mutant line, it used to investigate FMO response antidepressant imipramine, which has four major metabolites, three one, imipramine N-oxide, solely FMO1.Results On treatment with Imipramine, wild-type mice became sedated N-oxide brain other tissues. In contrast knockout did not produce but showed exaggerated pharmacological behavioural responses, such as tremor body spasm, had a higher concentration parent compound serum kidney there an increase desipramine brain.Conclusion The absence FMO1-mediated N-oxidation results enhanced central nervous system effects drug. provide insights into themetabolism may explain basis adverse reactions seen some patients. will valuable resource for defining FMO1 foreign chemicals. Pharmacogenetics Genomics 19:289-299 (C) 2009 Wolters Kluwer Health vertical bar Lippincott Williams & Wilkins.