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

Hernandez, Diana; Janmohamed, Azara; Chandan, Pritpal; Omar, Bilal; Phillips, Ian; Shephard, Elizabeth A.

doi:10.1097/fpc.0b013e328328d507

Cited by 23 publications

(25 citation statements)

References 47 publications

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“…If FMO1 activity catalyzed the N -oxidation of nicotine in the brains of smokers, the nicotine N -oxide formed could serve as a substrate pool available for reduction back to nicotine. The reduction of the N -oxide of tertiary amines has been suggested to play a role in the pharmacology of both imipramine and tamoxifen [20, 21]. …”

Section: Discussionmentioning

confidence: 99%

Common polymorphisms in FMO1 are associated with nicotine dependence

Hinrichs

Murphy

Wang

et al. 2011

Pharmacogenetics and Genomics

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BACKGROUND Cigarette smoking and other forms of tobacco use are the leading cause of preventable mortality in the world. A better understanding of the etiology of nicotine addiction may help increase the success rate of cessation and decrease the massive morbidity and mortality associated with smoking. METHODS In order to identify genetic polymorphisms that contribute to nicotine dependence, our group undertook a genetic association study including three enzyme families that potentially influence nicotine metabolism: cytochrome P450 enzymes (CYP P450s), flavin monooxygenases (FMOs) and UDP-glucuronosyl transferases (UGTs). RESULTS Several polymorphisms in FMO1 showed association in a discovery sample and were tested in an independent replication sample. One polymorphism, rs10912765, showed association that remained significant after Bonferroni correction (nominal p=0.0067, corrected p=0.0134). Several additional polymorphisms in linkage disequilibrium with this SNP also showed association. Subsequent in vitro experiments characterized FMO1 as a more efficient catalyst of nicotine N-oxidation than FMO3. In adult humans, FMO1 is primarily expressed in the kidney and is likely to be a major contributor to the renal metabolism and clearance of therapeutic drugs. FMO1 is also expressed in the brain and could contribute to the nicotine concentration in this tissue. CONCLUSIONS These findings suggest that polymorphisms in FMO1 are significant risk factors in the development of nicotine dependence and that the mechanism may involve variation in nicotine pharmacology.

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Section: Discussionmentioning

confidence: 99%

Common polymorphisms in FMO1 are associated with nicotine dependence

Hinrichs

Murphy

Wang

et al. 2011

Pharmacogenetics and Genomics

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“…Imipramine N-oxide undergoes retroreduction in vivo, thus, quantification of the oxygenated product in plasma or urine can miss or underestimate the contribution of FMO1 to overall metabolism and clearance of the drug. Using an Fmo1-null mouse model, imipramine was shown to cause sedation only in wild-type animals, i.e., those that produced imipramine N-oxide in brain [119]. Adverse behavioural changes, such as tremor, were observed only in mice that lacked FMO1 (the knockout mice), which produced higher amounts in brain of desipramine, a product of CYP-mediated metabolism. )…”

Section: Mouse Models For Fmo-mediated Drug Metabolismmentioning

confidence: 99%

“…can also help assess the contribution of a FMO protein to the metabolism of a drug that undergoes multi-pathway metabolism in vivo [120]. For instance, the antidepressant imipramine is oxygenated only by FMO1, to produce the N-oxide [119]. Imipramine N-oxide undergoes retroreduction in vivo, thus, quantification of the oxygenated product in plasma or urine can miss or underestimate the contribution of FMO1 to overall metabolism and clearance of the drug.…”

Section: Mouse Models For Fmo-mediated Drug Metabolismmentioning

confidence: 99%

Drug metabolism by flavin-containing monooxygenases of human and mouse

Phillips

Shephard

2016

Expert Opinion on Drug Metabolism & Toxicology

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“…This KO mouse, created by Hernandez et al [22,23], serves as a model for individuals with the FMO2*2 genotype (all Europeans and Asians, and most individuals of African and Hispanic origin). FMO2*2 expression produces a truncated protein, (FMO2.2), unable to bind FAD, that is catalytically inactive and thus will not metabolize ETA.…”

Section: Resultsmentioning

confidence: 99%

“…When Fmo1/2/4 null mice are dosed with imipramine, a drug metabolized by FMO1-dependent N -oxygenation, there were marked differences in drug effects and adverse health impacts of wild type versus knockout mice. The knockout mice showed pharmacological behavioral responses that did not occur in the wild type mice [23]. We are employing this Fmo1/2/4 triple knockout model as a platform to establish the impact in vivo of the absence of FMO-dependent metabolism from lung.…”

Section: Introductionmentioning

confidence: 99%

Metabolism and Pharmacokinetics of the Anti-Tuberculosis Drug Ethionamide in a Flavin-Containing Monooxygenase Null Mouse

et al. 2012

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Multiple drug resistance (MDR) in Mycobacterium tuberculosis (mTB), the causative agent for tuberculosis (TB), has led to increased use of second-line drugs, including ethionamide (ETA). ETA is a prodrug bioactivated by mycobacterial and mammalian flavin-containing monooxygenases (FMOs). FMO2 is the major isoform in the lungs of most mammals, including primates. In humans a polymorphism exists in the expression of FMO2. FMO2.2 (truncated, inactive) protein is produced by the common allele, while the ancestral allele, encoding active FMO2.1, has been documented only in individuals of African and Hispanic origin, at an incidence of up to 50% and 7%, respectively. We hypothesized that FMO2 variability in TB-infected individuals would yield differences in concentrations and ratios of ETA prodrug and metabolites. In this study we assessed the impact of the FMO2 genetic polymorphism on the pharmacokinetics of ETA after administration of a single oral dose of ETA (125 mg/kg) to wild type and triple Fmo1/2/4-null mice, measuring levels of prodrug vs. metabolites in plasma collected from 0 to 3.5 h post-gavage. All mice metabolized ETA to ETA S-oxide (ETASO) and 2-ethyl-4-amidopyridine (ETAA). Wild type mice had higher plasma concentrations of metabolites than of parent compound (p = 0.001). In contrast, Fmo1/2/4-null mice had higher plasma concentrations of parent compound than of metabolites (p = 0.0001). Thus, the human FMO2 genotype could impact the therapeutic efficacy and/or toxicity of ETA.

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

Cited by 23 publications

References 47 publications

Common polymorphisms in FMO1 are associated with nicotine dependence

Common polymorphisms in FMO1 are associated with nicotine dependence

Drug metabolism by flavin-containing monooxygenases of human and mouse

Metabolism and Pharmacokinetics of the Anti-Tuberculosis Drug Ethionamide in a Flavin-Containing Monooxygenase Null Mouse

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