Stereoselective sulfoxidation of sulindac sulfide by flavin-containing monooxygenases. Comparison of human liver and kidney microsomes and mammalian enzymes.

摘要: The stereoselective sulfoxidation of the pharmacologically active metabolite sulindac, sulindac sulfide, was characterized in human liver, kidney, and cDNA-expressed enzymes. Kinetic parameter estimates (pH = 7.4) for sulfoxide formation liver microsomes (N 4) R- S-sulindac were Vmax 1.5 ± 0.50 nmol/min/mg, Km 15 5.1 μM; 1.1 0.36 16 6.1 μM, respectively. Kidney 3) produced 0.9 0.29 2.9 0.5 0.21 22 1.9 μM sulfoxide, In flavin-containing monooxygenase 3 (FMO3) R-sulindac increased 60–70% at pH 8.5, but unchanged. fourteen microsomal preparations, significant correlations occurred between either immunoquantified FMO or nicotine N-oxidation (r 0.88 0.83; P < 0.01). rate also correlated significantly 0.85 0.75; 0.01) with thirteen kidney samples. Mild heat deactivation reduced activity by 30–60%, a loss stereoselectivity observed. Methimazole potent nonstereoselective inhibitor microsomes. n-Octylamine membrane solubilization lubrol selective inhibitors formation. CYPs failed to appreciably sulfoxidate CYP ineffective suppressing catalytic activity. Purified mini-pig FMO1, rabbit lung FMO2, FMO3 efficiently oxidized sulfide high degree towards R-isomer, FMO5 lacked biotransformation is catalyzed predominately FMOs may prove be useful characterizing