Peroxidase-Mediated Bioactivation of Hydroxylated Metabolites of Carbamazepine and Phenytoin
Peroxidase-Mediated Bioactivation of Hydroxylated Metabolites of Carbamazepine and Phenytoin
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过氧化物酶介导的卡马西平和苯妥英羟基化代谢物的生物活化
DOI：
10.1124/dmd.107.019554
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发表时间：
2008
影响因子：
3.9
通讯作者：
J. Uetrecht
中科院分区：
文献类型：
--
作者：
Wei Yang Lu;J. Uetrecht
卡马西平（CBZ）和苯妥英（PHN）与特异质药物反应的发生率相对较高相关。大多数这样的反应被认为是由于反应性代谢物。与这两种药物相关的反应是相似的，如果患者对其中一种药物有反应，他或她对另一种药物有反应的风险增加，这表明可能涉及类似的反应性代谢产物。CBZ在大约10%的患者中引起中性粒细胞减少症;这表明反应性代谢物是由髓过氧化物酶（MPO）形成的，髓过氧化物酶是中性粒细胞中的主要氧化酶。CBZ的主要代谢产物为2-和3-OH代谢产物，PHN的主要代谢产物为4-OH代谢产物。MPO/H_2O_2对2-OH-CBZ和3-OH-CBZ均有进一步的氧化作用，且3-OH-CBZ的氧化速度远快于2-OH-CBZ或CBZ本身的氧化速度。MPO氧化形成3-OH-CBZ和4-OH-PHN的二聚体，在N-乙酰酪氨酸存在下，形成交叉二聚体。这强烈表明自由基中间体。MPO/H_2O_2活化3-OH-CBZ和4-OH-PHN后，可与模型蛋白酪氨酸共价结合。自由基通常产生活性氧（ROS）。我们还测试了这些代谢物产生ROS的能力，发现3-OH-CBZ产生的ROS比2-OH-CBZ多，而2-OH-CBZ又比CBZ产生的ROS多。这些结果表明，生物激活3-OH-CBZ和4-OH-PHN自由基的过氧化物酶可能发挥作用的能力，这些药物引起特异质药物反应。
Carbamazepine (CBZ) and phenytoin (PHN) are associated with a relatively high incidence of idiosyncratic drug reactions. Most such reactions are believed to be due to reactive metabolites. The reactions associated with these two drugs are similar, and if a patient has a reaction to one, he or she is at increased risk of having a reaction to the other, suggesting that a similar reactive metabolite may be involved. CBZ causes neutropenia in approximately 10% of patients; this suggests that reactive metabolites are formed by myeloperoxidase (MPO), the major oxidative enzyme in neutrophils. Major metabolites of CBZ are the 2- and 3-OH metabolites, and that of PHN is the 4-OH metabolite. We found that both 2-OH-CBZ and 3-OH-CBZ were further oxidized by MPO/H2O2, and the oxidation of 3-OH-CBZ was much faster than the oxidation of 2-OH-CBZ or CBZ itself. Oxidation by MPO formed dimers of 3-OH-CBZ and 4-OH-PHN and, in the presence of N-acetyltyrosine, cross dimers were formed. This strongly suggests free radical intermediates. Bioactivation of 3-OH-CBZ and 4-OH-PHN by MPO/H2O2 led to covalent binding to the tyrosine of a model protein. Free radicals usually generate reactive oxygen species (ROS). We also tested the ability of these metabolites to generate ROS and found that 3-OH-CBZ generated more ROS than 2-OH-CBZ, which was, in turn, greater than that generated by CBZ. These results suggest that bioactivation of 3-OH-CBZ and 4-OH-PHN to free radicals by peroxidases may play a role in the ability of these drugs to cause idiosyncratic drug reactions.
影响因子：
5.6
作者：
ZENG, J;FENNA, RE
通讯作者：
FENNA, RE
DOI：
10.1016/s0021-9258(18)53581-x
发表时间：
1993-02
期刊：
The Journal of biological chemistry
影响因子：
--
作者：
J. Heinecke;Wei Li;Henry L. Daehnke;J. Goldstein
通讯作者：
J. Heinecke;Wei Li;Henry L. Daehnke;J. Goldstein