氯氮平相关的花生四烯酸代谢紊乱:氯氮平诱导的心脏毒性的未来方向。

IF 2.9 3区 医学 Q2 TOXICOLOGY
Ellen Kingston, Kathryn Burns, Malcolm Tingle
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引用次数: 0

摘要

氯氮平是一种有效的抗精神病药物,用于治疗难治性精神分裂症。然而,临床使用氯氮平是有限的,因为心脏毒性的风险,包括氯氮平引起的心肌炎。氯氮平的氧化和氯氮平n -氧化物的还原可以由心脏选择性细胞色素P450 (CYP)亚型CYP2J2、CYP1A1和CYP1B1催化,这些亚型也被报道代谢花生四烯酸。与cyp催化的花生四烯酸代谢的任何相互作用都可能扰乱促炎羟基二十碳四烯酸和抗炎环氧二十碳三烯酸的平衡,使心脏进入炎症状态。从而使其更容易受到可能诱发氯氮平诱导的心肌炎的损害。本初步研究的目的是研究花生四烯酸与氯氮平或氯氮平- n -氧化物之间的相互作用是否发生在CYP2J2、CYP1A1和CYP1B1位点,而不是肝脏同种异构体CYP2C19。我们的研究结果表明,CYP1B1催化花生四烯酸代谢明显受到干扰,在氯氮平和氯氮平n-氧化物存在下,代谢物形成呈浓度依赖性减少。与单独使用氯氮平孵育相比,每种异构体的n -去甲基氯氮平形成减少,氯氮平和氯氮平- n -氧化物氧化还原循环能力受损。尽管受分析灵敏度的限制,这些数据提供了花生四烯酸和氯氮平之间代谢相互作用的明确证据。这为解释氯氮平诱导的心肌炎患者的易感性和心脏选择性炎症的可行机制提供了一个新的假设。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
Clozapine-associated perturbation of arachidonic acid metabolism: A future direction for clozapine-induced cardiotoxicity
Clozapine is an effective antipsychotic medication utilised for treatment-resistant schizophrenia. However, clinical use of clozapine is limited due to the risk of cardiotoxicities, including clozapine-induced myocarditis. Oxidation of clozapine and reduction of clozapine-N-oxide can be catalysed by the cardio-selective cytochrome P450 (CYP) isoforms CYP2J2, CYP1A1 and CYP1B1, which are also reported to metabolise arachidonic acid. Any interaction with CYP-catalysed arachidonic acid metabolism may perturb the balance of pro-inflammatory hydroxyeicosatetraenoic acids and anti-inflammatory epoxyeicosatrienoic acids, priming the heart to an inflammatory state. Thereby making it more susceptible to the damage that may induce clozapine-induced myocarditis. The purpose of this preliminary study was to investigate whether an interaction between arachidonic acid and clozapine or clozapine-N-oxide occurs at CYP2J2, CYP1A1 and CYP1B1, in comparison to the hepatic isoform CYP2C19. Our results demonstrated a clear perturbation of CYP1B1 catalysed arachidonic acid metabolism, with a concentration-dependent decrease in metabolite formation in the presence of clozapine and clozapine-N-oxide. Each isoform also had decreased N-desmethylclozapine formation relative to incubations with clozapine alone and impaired clozapine and clozapine-N-oxide REDOX cycling capacity. Although limited by analytical sensitivity, these data provide clear evidence of a metabolic interaction between arachidonic acid and clozapine. This offers a novel hypothesis to explain patient susceptibility and a feasible mechanism for the cardiac-selective inflammation observed in clozapine-induced myocarditis.
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来源期刊
Toxicology letters
Toxicology letters 医学-毒理学
CiteScore
7.10
自引率
2.90%
发文量
897
审稿时长
33 days
期刊介绍: An international journal for the rapid publication of novel reports on a range of aspects of toxicology, especially mechanisms of toxicity.
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