Bhamre S, Bhagwat S V, Shankar S K, Williams D E, Ravindranath V
Department of Neurochemistry, National Institute of Mental Health and Neuro Sciences, Bangalore, India.
J Pharmacol Exp Ther. 1993 Oct;267(1):555-9.
Flavin-containing monooxygenase (FMO)-mediated oxidation of the model substrates N,N-dimethylaniline and methimazole, and the antidepressants imipramine and fluoxetine, was determined in rat brain microsomes. No sex-related difference was observed in the activity of the FMO-mediated metabolism of the four substrates examined. The Km values for flavin-containing monooxygenase-mediated metabolism of N,N-dimethylaniline and methimazole were 2.8 and 0.8 mM, respectively, and the Km values for the oxidation of the antidepressants imipramine and fluoxetine were 20.9 and 9.8 microM, respectively. The Vmax values for oxidation of N,N-dimethylaniline, methimazole, imipramine and fluoxetine were 340, 31, 182 and 470 nmol nicotinamide adenine dinucleotide phosphate oxidized/min/mg protein, respectively. Western immunoblot analysis using antisera to purified porcine liver FMO did not reveal any immunological cross-reactivity with male or female brain microsomal protein. Antibody to rabbit lung flavin-containing monooxygenase cross-reacted with brain microsomes as examined by Western immunoblot studies. Addition of the antibody raised against rabbit lung FMO resulted in inhibition (43% inhibition) of the FMO-mediated metabolism of imipramine. Immunocytochemical examination of rat brain sections using the above antibody revealed the preferential localization of flavin-containing monooxygenase in the neuronal cell body. The flavin-containing monooxygenase-mediated metabolism of antidepressant drugs by brain microsomes is of profound pharmacological significance.
在大鼠脑微粒体中测定了含黄素单加氧酶（FMO）介导的模型底物N，N - 二甲基苯胺和甲巯咪唑以及抗抑郁药丙咪嗪和氟西汀的氧化反应。在所检测的四种底物的FMO介导的代谢活性中未观察到性别相关差异。FMO介导的N，N - 二甲基苯胺和甲巯咪唑代谢的Km值分别为2.8和0.8 mM，抗抑郁药丙咪嗪和氟西汀氧化的Km值分别为20.9和9.8 microM。N，N - 二甲基苯胺、甲巯咪唑、丙咪嗪和氟西汀氧化的Vmax值分别为340、31、182和470 nmol烟酰胺腺嘌呤二核苷酸磷酸氧化/分钟/毫克蛋白。使用针对纯化猪肝FMO的抗血清进行的蛋白质免疫印迹分析未显示与雄性或雌性脑微粒体蛋白有任何免疫交叉反应。通过蛋白质免疫印迹研究检测，兔肺含黄素单加氧酶抗体与脑微粒体发生交叉反应。添加针对兔肺FMO产生的抗体导致丙咪嗪的FMO介导的代谢受到抑制（43%抑制）。使用上述抗体对大鼠脑切片进行免疫细胞化学检查显示含黄素单加氧酶在神经元细胞体中优先定位。脑微粒体中含黄素单加氧酶介导的抗抑郁药代谢具有深远的药理学意义。
