Cell-, tissue-, sex- and developmental stage-specific expression of mouse flavin-containing monooxygenases (Fmos)

Janmohamed, Azara; Hernandez, Diana; Phillips, Ian; Shephard, Elizabeth A.

doi:10.1016/j.bcp.2004.02.036

Cited by 107 publications

(119 citation statements)

References 46 publications

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“…However, in contrast to the 2004 study [26], we found Fmo2 transcript levels to be about 1.7-fold higher than Fmo1 transcript levels in mouse lung. We did not detect strain differences in the pattern of FMO isoforms expressed.…”

Section: Discussioncontrasting

confidence: 99%

“…Our findings verify that there is significant production of Fmo1 transcript in mouse lung, which is in keeping with both earlier studies [25,26]. However, in contrast to the 2004 study [26], we found Fmo2 transcript levels to be about 1.7-fold higher than Fmo1 transcript levels in mouse lung.…”

Section: Discussionsupporting

confidence: 92%

“…If correct, recent findings [26] indicating that Fmo2 transcript was nearly absent from the lungs of 129 and C57 mice, from 0 to 8 weeks of age, would render meaningless any efforts to develop an Fmo2 knockout mouse. We hypothesized that strain differences might exist that would account for the lack of Fmo2 transcript they measured and would explain the presence of both Fmo2 transcript and Fmo2 enzyme activity from the lungs of ICR (CD-1) mice [25].…”

Section: Discussionmentioning

confidence: 99%

“…We included mice from these three strains in our study and added five additional strains. We worked with eight-week old mice and used the same forward and reverse primer sequences for Fmo1, Fmo3 and Fmo5 as were used to isolate cDNA clones for RNAse protection studies [26]. When we initiated the study, we designed a different set of primers for Fmo2, as the published forward primer sequence did not match (28.5% overall mismatch; 11.1% 3' end mismatch) NCBI's Fmo2 cDNA reference sequence (NM_018881).…”

Section: Discussionmentioning

confidence: 99%

“…A 1992 study [25] demonstrated the presence of Fmo1 and Fmo2 transcript and protein in lung. More recently, a study of FMO gene expression in mice identified Fmo1 not Fmo2 as the major lung isoform [26]. We conducted this study to determine whether we could identify a mouse strain that primarily produced Fmo2 in the lung, as Fmo2 substrates would likely also be substrates for Fmo1, and would thus confound studies of Fmo2.…”

Section: Introductionmentioning

confidence: 99%

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Characterization of mouse flavin-containing monooxygenase transcript levels in lung and liver, and activity of expressed isoforms

Siddens

Henderson

VanDyke

et al. 2008

Biochemical Pharmacology

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The significance of active vs. inactive flavin-containing monooxygenase 2 (FMO2) for human drug and xenobiotic metabolism and sensitivity is unknown, but the underlying ethnic polymorphism is well documented. We used quantitative real-time PCR to measure message levels of Fmo1, Fmo2, Fmo3 and Fmo5 in lung and liver from eight strains of eight week old female mice to determine if a strain could be identified that predominately expressed Fmo2 in lung, recapitulating the human FMO expression profile and being the ideal strain for Fmo2 knockout studies. We also characterized enzyme activity of baculovirus expressed mouse Fmo1, Fmo2 and Fmo3 to identify a substrate or incubation conditions capable of discriminating Fmo2 from Fmo mixtures. Fmo transcript expression patterns were similar for all strains. In lung, 59% of total FMO message was Fmo2, but Fmo1 levels were also high, averaging 34%, whereas Fmo3 and Fmo5 levels were 2 and 5%, respectively. In liver, Fmo1, Fmo2, Fmo3 and Fmo5 contributed 16, 1, 7 and 76% respectively, of detected message. Peak activity varied by isoform and was pH-and substrate-dependent. Fmo3 oxidation of methyl ptolyl sulfide was negligible at pH 9.5, but Fmo3 oxidation of methimazole was comparable to Fmo1 and Fmo2. Heating microsomes at 50 °C for 10 min eliminated most Fmo1 and Fmo3 activity, while 94% of Fmo2 activity remained. Measurement of activity in heated and unheated lung and liver microsomes verified relative transcript abundance. Our results show that dual Fmo1/2 knockouts will be required to model the human lung FMO profile.

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Section: Discussioncontrasting

confidence: 99%