Modulatory effects of 5-fluorouracil on the rhythmic expression of circadian clock genes: A possible mechanism of chemotherapy-induced circadian rhythm disturbances
Modulatory effects of 5-fluorouracil on the rhythmic expression of circadian clock genes: A possible mechanism of chemotherapy-induced circadian rhythm disturbances
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DOI：
10.1016/j.bcp.2008.01.011
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发表时间：
2008-04-15
影响因子：
5.8
通讯作者：
Ohdo, Shigehiro
中科院分区：
文献类型：
--
作者：
Terazonoa, Hideyuki;Hamdan, Ahmed;Ohdo, Shigehiro
生物钟系统是适应环境条件每日变化的内源生理功能所必需的。昼夜节律的异常，如睡眠-觉醒周期和激素分泌的时间，与各种生理和精神障碍有关。最近的分子研究表明，特定时钟基因转录的振荡在24小时生理和行为周期的产生中起着核心作用。人们已经注意到，接受化疗药物的患者会经历行为和身体表现的障碍，包括昼夜节律。为了探讨化疗药物引起这些节律紊乱的潜在机制，我们研究了治疗癌症的最广泛的化疗药物之一5-氟尿嘧啶(5-FU)对时钟基因表达的影响。用5-FU处理培养的NIH3T3细胞48h后，PER1和PER2的mRNA水平显著降低，但不影响细胞的存活率，但同样剂量的尿嘧啶(与5FU的结构类似物)对时钟基因的表达几乎没有影响。与其抑制作用一致的是，小鼠连续给予5-FU(2 mg/kg/h)可减弱PER1和PER2在肝脏和视交叉上核(哺乳动物生物钟的中心)表达的振荡。这些结果揭示了化疗药物5-FU对生物钟机制的可能药理作用，这是其对24小时生理和行为节律产生不利影响的根本原因。(C)2008 Elsevier Inc.保留所有权利。
The circadian clock system is necessary to adapt endogenous physiological functions to daily variations in environmental conditions. Abnormality in circadian rhythms, such as the sleep-wake cycle and the timing of hormonal secretions, is implicated in various physiological and psychiatrical disorders. Recent molecular studies have revealed that oscillation in the transcription of specific clock genes plays a central role in the generation of 24 h cycles of physiology and behavior. It has been noticed that patients receiving chemotherapeutic agents experience disturbances in their behavioral and physical performances, including circadian rhythms. To explore the underlying mechanism of chemotherapeutic agent-induced disturbance of these rhythms, we investigated the influence of 5-fluorouracil (5FU), one of the most widely used chemotherapeutic agents for the treatment of cancers, on the expression of clock genes. Treatment of cultured NIH3T3 cells with 5-FU for 48 h resulted in a significant reduction of mRNA levels of Period1 (Per1) and Period2 (Per2) without affecting cell viability; however, treatment with the same amount of uracil, a structural analog of 5FU, had little effect on the expression of clock genes. Consistent with its inhibitory actions, continuous administration of 5-FU (2 mg/kg/h) to mice attenuated the oscillation in the expressions of Per1 and Per2 in the liver and suprachiasmatic nuclei, the center of the mammalian circadian clock. These results reveal a possible pharmacological action by the chemotherapeutic agent 5-FU on the circadian clock mechanism, which is the underlying cause of its adverse effects on 24-h rhythms of physiology and behavior. (c) 2008 Elsevier Inc. All rights reserved.