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


CONCLUSIONS
The absence of FMO1-mediated N-oxidation of imipramine results in enhanced central nervous system effects of the drug. The results provide insights into the metabolism 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.
Hernandez
Diana
D
Department of Biochemical Engineering, Institute of Structural and Molecular Biology, University College London, London, UK.
Janmohamed
Azara
A
Chandan
Pritpal
P
Omar
Bilal A
BA
Phillips
Ian R
IR
Shephard
Elizabeth A
EA
D000818:Animals; D000929:Antidepressive Agents, Tricyclic / Q000378:metabolism / Q000494:pharmacology*; D001522:Behavior, Animal / Q000187:drug effects*; D002478:Cells, Cultured; D002875:Chromosomes / Q000235:genetics; D053595:Embryonic Stem Cells / Q000166:cytology*; D005260:Female; D017353:Gene Deletion; D006579:Heterozygote; D006720:Homozygote; D007099:Imipramine / Q000031:analogs & derivatives / Q000378:metabolism / Q000494:pharmacology*; D019426:Integrases / Q000235:genetics; D008297:Male; D051379:Mice; D010105:Oxygenases / Q000172:deficiency / Q000235:genetics*; D013035:Spasm / Q000139:chemically induced; D014162:Transfection; D014202:Tremor / Q000139:chemically induced
D000929:Antidepressive Agents, Tricyclic; C002921:imipramine N-oxide; D010105:Oxygenases; C020066:dimethylaniline monooxygenase (N-oxide forming); C045073:Cre recombinase; D019426:Integrases; D007099:Imipramine