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首页> 外文期刊>Biochemical Pharmacology >Stereoselective sulfoxidation of sulindac sulfide by flavin-containing monooxygenases. Comparison of human liver and kidney microsomes and mammalian enzymes.
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Stereoselective sulfoxidation of sulindac sulfide by flavin-containing monooxygenases. Comparison of human liver and kidney microsomes and mammalian enzymes.

机译：含有黄素的单加氧酶对舒林酸硫化物的立体选择性硫氧化。人肝和肾微粒体与哺乳动物酶的比较。

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摘要

The stereoselective sulfoxidation of the pharmacologically active metabolite of sulindac, sulindac sulfide, was characterized in human liver, kidney, and cDNA-expressed enzymes. Kinetic parameter estimates (pH = 7.4) for sulindac sulfoxide formation in human liver microsomes (N = 4) for R- and S-sulindac sulfoxide were V(max) = 1.5 +/- 0.50 nmol/min/mg, K(m) = 15 +/- 5.1 microM; and V(max) = 1.1 +/- 0.36 nmol/min/mg, K(m) = 16 +/- 6.1 microM, respectively. Kidney microsomes (N = 3) produced parameter estimates (pH = 7.4) of V(max) = 0.9 +/- 0.29 nmol/min/mg, K(m) = 15 +/- 2.9 microM; V(max) = 0.5 +/- 0.21 nmol/min/mg, K(m) = 22 +/- 1.9 microM for R- and S-sulindac sulfoxide, respectively. In human liver and flavin-containing monooxygenase 3 (FMO3) the V(max) for R-sulindac sulfoxide increased 60-70% at pH = 8.5, but for S-sulindac sulfoxide was unchanged. In fourteen liver microsomal preparations, significant correlations occurred between R-sulindac sulfoxide formation and either immunoquantified FMO or nicotine N-oxidation (r = 0.88 and 0.83; P < 0.01). The R- and S-sulindac sulfoxide formation rate also correlated significantly (r = 0.85 and 0.75; P < 0.01) with immunoquantified FMO in thirteen kidney microsomal samples. Mild heat deactivation of microsomes reduced activity by 30-60%, and a loss in stereoselectivity was observed. Methimazole was a potent and nonstereoselective inhibitor of sulfoxidation in liver and kidney microsomes. n-Octylamine and membrane solubilization with lubrol were potent and selective inhibitors of S-sulindac sulfoxide formation. cDNA-expressed CYPs failed to appreciably sulfoxidate sulindac sulfide, and CYP inhibitors were ineffective in suppressing catalytic activity. Purified mini-pig liver FMO1, rabbit lung FMO2, and human cDNA-expressed FMO3 efficiently oxidized sulindac sulfide with a high degree of stereoselectivity towards the R-isomer, but FMO5 lacked catalytic activity. The biotransformation of the sulfide to the sulfoxide is catalyzed predominately by FMOs and may prove to be useful in characterizing FMO activity.
机译：在人类肝脏，肾脏和cDNA表达的酶中表征了舒林酸的药理活性代谢物，舒林酸硫化物的立体选择性硫氧化。 R-和S-舒林酸亚砜在人肝微粒体（N = 4）中形成舒林酸亚砜的动力学参数估计值（pH = 7.4）为V（max）= 1.5 +/- 0.50 nmol / min / mg，K（m） = 15 +/- 5.1 microM;和V（max）= 1.1 +/- 0.36 nmol / min / mg，K（m）= 16 +/- 6.1 microM。肾脏微粒体（N = 3）产生的参数估计值（pH = 7.4）的V（max）= 0.9 +/- 0.29 nmol / min / mg，K（m）= 15 +/- 2.9 microM;对于R-和S-舒林酸亚砜，V（最大）= 0.5 +/- 0.21 nmol / min / mg，K（m）= 22 +/- 1.9 microM。在人肝脏和含黄素的单加氧酶3（FMO3）中，R-舒林酸亚砜的V（max）在pH = 8.5时增加60-70％，但S-舒林酸亚砜的V（max）不变。在14种肝微粒体制剂中，R-舒林酸亚砜的形成与免疫定量FMO或尼古丁N-氧化之间存在显着相关性（r = 0.88和0.83; P <0.01）。 R-和S-舒林酸亚砜的形成速率也与免疫定量的FMO在13个肾脏微粒体样品中显着相关（r = 0.85和0.75; P <0.01）。微粒体的轻度失活使活性降低了30-60％，并且观察到立体选择性的损失。甲基咪唑是肝和肾微粒体中一种有效且非立体选择性的亚砜氧化抑制剂。正辛胺和lubrol的膜增溶是S-舒林酸亚砜形成的有效和选择性抑制剂。 cDNA表达的CYP不能明显地使硫化舒灵酸硫化物氧化，而CYP抑制剂在抑制催化活性方面无效。纯化的小猪肝FMO1，兔肺FMO2和表达人cDNA的FMO3有效氧化了舒林酸硫化物，并对R-异构体具有高度立体选择性，但FMO5缺乏催化活性。硫化物向亚砜的生物转化主要是由FMO催化的，并可能被证明可用于表征FMO活性。

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