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The overlooked contribution of Flavin‐containing Monoxygenases in the determination of total metabolic flux
Author(s) -
Kousba Ahmed A,
Stewart Joshua,
Soll Richard,
Martin Michael
Publication year - 2008
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.22.1_supplement.920.4
Subject(s) - microsome , gene isoform , flux (metallurgy) , cytochrome p450 , flavin containing monooxygenase , metabolic pathway , cyp3a4 , drug metabolism , chemistry , biochemistry , metabolism , metabolic flux analysis , enzyme , monooxygenase , gene , organic chemistry
Purpose: The purpose of the current study was to assess the relative contribution of flavin‐containing monoxygenases (FMO) and CYP‐mediated pathways with respect to total metabolic flux of selected compounds. Methods: The contribution of FMO and CYP in hepatic metabolic flux was assessed in human liver microsomes in the presence of CYP and FMO isoform specific inhibitors. In addition, FMO heat sensitivity was also employed in liver microsomal evaluation. The reaction phenotyping was further refined using individual human recombinant CYP and FMO isoforms. The metabolic flux through each identified pathway was normalized to the content of the individual CYP and FMO isoform in human liver microsomes and expressed as % Total Normalized Rate (%TNR). Results: A marked contribution of FMO in the total metabolic flux of the selected compounds (~50%) was observed. The normalization of the metabolic rates to the CYP and FMO isoform contents suggests that CYP3A4 and FMO3 are the main isoforms responsible for the compounds in vitro metabolism (87–99%). Conclusions: While FMO isoforms play an important role in drug metabolism, most literature based approaches for reaction phenotyping primarily evaluate CYP‐mediated metabolism. In the current study, CYP and FMO demonstrated comparable contribution total metabolic flux of the selected compounds. The marked contribution of FMO metabolism of the selected compounds may provide an advantageous property for minimizing the potential for adverse drug‐drug interactions. FMO isoforms are not readily induced nor inhibited by drugs or environmental chemicals.