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

Hernandez, D; Janmohamed, A; Chandan, P; Omar, BA; Phillips, IR; Shephard, EA; (2009) Deletion of the mouse Fmo1 gene results in enhanced pharmacological behavioural responses to imipramine. PHARMACOGENET GENOM , 19 (4) 289 - 299. 10.1097/FPC.0b013e328328d507.

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Abstract

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

Type: Article
Title: Deletion of the mouse Fmo1 gene results in enhanced pharmacological behavioural responses to imipramine
DOI: 10.1097/FPC.0b013e328328d507
Keywords: behavioural response, chromosomal engineering, drug metabolism, flavin-containing monooxygenase, imipramine, knockout mice, pharmacogenetics, FLAVIN-CONTAINING MONOOXYGENASES, PERFORMANCE LIQUID-CHROMATOGRAPHY, N-OXIDE, HUMAN LIVER, METABOLISM, EXPRESSION, PLASMA, DESIPRAMINE, MICE, POLYMORPHISM
UCL classification: UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences > Div of Biosciences > Structural and Molecular Biology
UCL > Provost and Vice Provost Offices > UCL BEAMS > Faculty of Engineering Science > Dept of Biochemical Engineering
URI: http://discovery.ucl.ac.uk/id/eprint/182826
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