de Vries E M, Oosterman J E, Eggink H M, de Goede P, Sen S, Foppen E, Boudzovitch-Surovtseva O, Boelen A, Romijn J A, laFleur S E, Kalsbeek A
Department of Medicine, Academic Medical Center, Amsterdam, the Netherlands.
Department of Endocrinology and Metabolism, Academic Medical Center, Amsterdam, the Netherlands.
PLoS One. 2017 Oct 2;12(10):e0185520. doi: 10.1371/journal.pone.0185520. eCollection 2017.
With chronotherapy, drug administration is synchronized with daily rhythms in drug clearance and pharmacokinetics. Daily rhythms in gene expression are centrally mastered by the suprachiasmatic nucleus of the hypothalamus as well as by tissue clocks containing similar molecular mechanisms in peripheral organs. The central timing system is sensitive to changes in the external environment such as those of the light-dark cycle, meal timing and meal composition. We investigated how changes in diet composition and meal timing would affect the daily hepatic expression rhythms of the nuclear receptors PXR and CAR and of enzymes involved in P450 mediated drug metabolism, as such changes could have consequences for the practice of chronotherapy.
Rats were subjected to either a regular chow or a free choice high-fat-high-sugar (fcHFHS) diet. These diets were provided ad libitum, or restricted to either the light phase or the dark phase. In a second experiment, rats had access to chow either ad libitum or in 6 meals equally distributed over 24 hours.
Pxr, Alas1 and Por displayed significant day-night rhythms under ad libitum chow fed conditions, which for Pxr was disrupted under fcHFHS diet conditions. Although no daily rhythms were detected in expression of CAR, Cyp2b2 and Cyp3a2, the fcHFHS diet did affect basal expression of these genes. In chow fed rats, dark phase feeding induced a diurnal rhythm in Cyp2b2 expression while light phase feeding induced a diurnal rhythm in Car expression and completely shifted the peak expression of Pxr, Car, Cyp2b2, Alas1 and Por. The 6-meals-a-day feeding only abolished the Pxr rhythm but not the rhythms of the other genes.
We conclude that although nuclear receptors and enzymes involved in the regulation of hepatic drug metabolism are sensitive to meal composition, changes in meal timing are mainly effectuated via changes in the molecular clock.
在时间治疗中，药物给药与药物清除及药代动力学的每日节律同步。基因表达的每日节律由下丘脑的视交叉上核以及外周器官中含有类似分子机制的组织时钟集中控制。中央计时系统对外部环境的变化敏感，如明暗周期、进餐时间和膳食组成的变化。我们研究了饮食组成和进餐时间的变化如何影响核受体PXR和CAR以及参与P450介导的药物代谢的酶的每日肝脏表达节律，因为这些变化可能会对时间治疗的实践产生影响。
将大鼠分为常规饲料组或自由选择的高脂肪高糖（fcHFHS）饮食组。这些饮食可随意提供，或限制在光照期或黑暗期。在第二个实验中，大鼠可随意进食或在24小时内平均分配为6餐进食。
在随意喂食常规饲料的条件下，Pxr、Alas1和Por显示出显著的昼夜节律，而在fcHFHS饮食条件下，Pxr的昼夜节律被破坏。虽然未检测到CAR、Cyp2b2和Cyp3a2表达的每日节律，但fcHFHS饮食确实影响了这些基因的基础表达。在喂食常规饲料的大鼠中，黑暗期喂食诱导了Cyp2b2表达的昼夜节律，而光照期喂食诱导了Car表达的昼夜节律，并完全改变了Pxr, Car, Cyp2b2, Alas1和Por的峰值表达。一天6餐喂食仅消除了Pxr的节律，而没有消除其他基因的节律。
我们得出结论，虽然参与肝脏药物代谢调节的核受体和酶对膳食组成敏感，但进餐时间的变化主要是通过分子时钟的变化来实现的。
