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Abstract：
BACKGROUND: Our recent studies showed that prolonged administration of novel atypical antipsychotics affected the expression and activity of cytochrome P450 (CYP), as demonstrated in vitro on human hepatocytes and in vivo on the rat liver. The aim of the present work was to study the effect of repeated treatment with asenapine, iloperidone, and lurasidone on the expression of transcription factors regulating CYP drug-metabolizing enzymes in rat liver.
METHODS: The hepatic mRNA (qRT-PCR) and protein levels (Western blotting) of aryl hydrocarbon receptor (AhR), pregnane X receptor (PXR), constitutive androstane receptor (CAR) and peroxisome proliferator-activated receptor (PPARγ) were measured in male Wistar rats after 2 week-treatment with asenapine, iloperidone or lurasidone.
RESULTS: The 2-week treatment with asenapine significantly diminished the AhR and PXR expression (mRNA, protein level), and CAR mRNA level in rat liver. Iloperidone lowered the AhR and CAR expression and PXR protein level. Lurasidone did not affect the expression of AhR and CAR, but increased PXR expression. The antipsychotics did not affect PPARγ.
CONCLUSIONS: Prolonged treatment with asenapine, iloperidone, or lurasidone affects the expression of transcription factors regulating the CYP drug-metabolizing enzymes. The changes in the expression of AhR, CAR, and PXR mostly correlate with alterations in the expression and activity of respective CYP enzymes found in our previous studies. Since these transcription factors are also engaged in the expression of phase II drug metabolism and drug transporters, changes in their expression may affect the metabolism of endogenous substrates and pharmacokinetics of concomitantly used drugs.
METHODS: The hepatic mRNA (qRT-PCR) and protein levels (Western blotting) of aryl hydrocarbon receptor (AhR), pregnane X receptor (PXR), constitutive androstane receptor (CAR) and peroxisome proliferator-activated receptor (PPARγ) were measured in male Wistar rats after 2 week-treatment with asenapine, iloperidone or lurasidone.
RESULTS: The 2-week treatment with asenapine significantly diminished the AhR and PXR expression (mRNA, protein level), and CAR mRNA level in rat liver. Iloperidone lowered the AhR and CAR expression and PXR protein level. Lurasidone did not affect the expression of AhR and CAR, but increased PXR expression. The antipsychotics did not affect PPARγ.
CONCLUSIONS: Prolonged treatment with asenapine, iloperidone, or lurasidone affects the expression of transcription factors regulating the CYP drug-metabolizing enzymes. The changes in the expression of AhR, CAR, and PXR mostly correlate with alterations in the expression and activity of respective CYP enzymes found in our previous studies. Since these transcription factors are also engaged in the expression of phase II drug metabolism and drug transporters, changes in their expression may affect the metabolism of endogenous substrates and pharmacokinetics of concomitantly used drugs.
摘要：
背景：我们最近的研究表明，新型非典型抗精神病药的长期给药影响细胞色素P450（CYP）的表达和活性，如体外在人肝细胞和体内在大鼠肝脏上所证明的。本工作的目的是研究阿塞那平重复治疗的效果，伊潘立酮,和lurasidone对大鼠肝脏中调节CYP药物代谢酶的转录因子表达的影响。
方法：芳烃受体（AhR）的肝脏mRNA（qRT-PCR）和蛋白质水平（Western印迹），孕烷X受体（PXR），用阿塞那平治疗2周后，在雄性Wistar大鼠中测量了组成性雄甾烷受体（CAR）和过氧化物酶体增殖物激活受体（PPARγ），伊潘立酮或鲁拉西酮。
结果：阿塞那平治疗2周显著降低了AhR和PXR的表达（mRNA，蛋白质水平)，和大鼠肝脏中的CARmRNA水平。依哌酮降低了AhR和CAR表达以及PXR蛋白水平。Lurasidone不影响AhR和CAR的表达，但PXR表达增加。抗精神病药物不影响PPARγ。
结论：阿塞那平长期治疗，伊潘立酮,或鲁拉西酮影响调节CYP药物代谢酶的转录因子的表达。AhR表达的变化，汽车,和PXR主要与我们先前研究中发现的相应CYP酶的表达和活性变化相关。由于这些转录因子还参与了Ⅱ期药物代谢和药物转运体的表达，它们表达的变化可能会影响内源性底物的代谢和伴随使用的药物的药代动力学。
方法：芳烃受体（AhR）的肝脏mRNA（qRT-PCR）和蛋白质水平（Western印迹），孕烷X受体（PXR），用阿塞那平治疗2周后，在雄性Wistar大鼠中测量了组成性雄甾烷受体（CAR）和过氧化物酶体增殖物激活受体（PPARγ），伊潘立酮或鲁拉西酮。
结果：阿塞那平治疗2周显著降低了AhR和PXR的表达（mRNA，蛋白质水平)，和大鼠肝脏中的CARmRNA水平。依哌酮降低了AhR和CAR表达以及PXR蛋白水平。Lurasidone不影响AhR和CAR的表达，但PXR表达增加。抗精神病药物不影响PPARγ。
结论：阿塞那平长期治疗，伊潘立酮,或鲁拉西酮影响调节CYP药物代谢酶的转录因子的表达。AhR表达的变化，汽车,和PXR主要与我们先前研究中发现的相应CYP酶的表达和活性变化相关。由于这些转录因子还参与了Ⅱ期药物代谢和药物转运体的表达，它们表达的变化可能会影响内源性底物的代谢和伴随使用的药物的药代动力学。
