TY - JOUR T1 - Size Limits of Thiocarbamides Accepted as Substrates by Human Flavin-Containing Monooxygenase 1 JF - Drug Metabolism and Disposition JO - Drug Metab Dispos SP - 1003 LP - 1006 VL - 28 IS - 8 AU - Young Mi Kim AU - Daniel M. Ziegler Y1 - 2000/08/01 UR - http://dmd.aspetjournals.org/content/28/8/1003.abstract N2 - Microsomes isolated from Spodoptera frugiperda (Sf)9 cells infected with human flavin-containing monooxygenase (FMO)1 recombinant baculovirus catalyzed the NADPH- and O2-dependent oxidation of methimazole, thiourea, and phenylthiourea. However, there was no detectable activity with 1,3-diphenylthiourea or larger thiocarbamides. Microsomes from control Sf9 cells were devoid of methimazole or thioureaS-oxygenase activity. Trimethylamine up to 1.0 mM had no detectable effect on the oxidation of 10 μM methimazole (Km = 5 μM) but 1.0 mMN,N-dimethylaniline or chlorpromazine inhibited the oxidation of 1.0 mM methimazole 50 and 70%, respectively. Although products were not isolated, the pronounced inhibition of methimazole S-oxygenation suggests that these amines are alternate substrates for human FMO1. Because 1,3-diphenylthiourea is apparently completely excluded from the catalytic site, tricyclic amine drugs are probably approaching the upper size limits of xenobiotics accepted by human FMO1. The substrate specificity of this isoform in humans appears considerably more restricted than that of pig or guinea pig FMO1. Differences in the size of nucleophiles accepted must be considered in attempting to extrapolate the extensive structure-activity studies available for pig FMO1 to this FMO isoform in humans. The American Society for Pharmacology and Experimental Therapeutics ER -