Abstract：
Human pregnane X receptor (PXR) is critical for regulating the expression of key drug-metabolizing enzymes such as CYP3A and CYP2C. Our recent study revealed that treatment with rodent-specific PXR agonist pregnenolone-16α-carbonitrile (PCN) significantly induced hepatomegaly and promoted liver regeneration after two-thirds partial hepatectomy (PHx) in mice. However, it remains unclear whether PXR activation induces hepatomegaly and liver regeneration and simultaneously promotes metabolic function of the liver. Here, we investigated the metabolism activity of CYP1A2, CYP3A1/2 and CYP2C6/11 during PXR activation-induced liver enlargement and regeneration in rats after cocktail dosing of CYP probe drugs. For PCN-induced hepatomegaly, a notable increase in the metabolic activity of CYP3A1/2 and CYP2C6/11, as evidenced by the plasma exposure of probe substrates and the AUC ratios of the characteristic metabolites to its corresponding probe substrates. The metabolic activity of CYP1A2, CYP3A1/2 and CYP2C6/11 decreased significantly after PHx. However, PCN treatment obviously enhanced the metabolic activity of CYP2C6/11 and CYP3A1/2 in PHx rats. Furthermore, the protein expression levels of CYP3A1/2 and CYP2C6/11 in liver were up-regulated. Taken together, this study demonstrates that PXR activation not only induces hepatomegaly and liver regeneration in rats, but also promotes the protein expression and metabolic activity of the PXR downstream metabolizing enzymes such as CYP3A1/2 and CYP2C6/11 in the body.
摘要：
人类孕烷X受体（PXR）对于调节关键药物代谢酶如CYP3A和CYP2C的表达至关重要。我们最近的研究表明，在小鼠三分之二部分肝切除术（PHx）后，用啮齿动物特异性PXR激动剂孕烯醇酮-16α-甲腈（PCN）治疗可显着诱导肝肿大并促进肝再生。然而,目前尚不清楚PXR激活是否诱导肝肿大和肝再生,同时促进肝脏的代谢功能.这里,我们研究了CYP1A2，CYP3A1/2和CYP2C6/11在PXR激活诱导的大鼠肝脏扩大和再生过程中的代谢活性。对于PCN诱导的肝肿大，CYP3A1/2和CYP2C6/11的代谢活性显着增加，如探针底物的血浆暴露以及特征性代谢物与其相应探针底物的AUC比率所证明的。PHx后CYP1A2、CYP3A1/2和CYP2C6/11的代谢活性显著下降。然而,PCN处置明显加强了PHx年夜鼠CYP2C6/11和CYP3A1/2的代谢活性。此外，肝脏CYP3A1/2和CYP2C6/11蛋白表达上调。一起来看,这项研究表明，PXR激活不仅诱导大鼠肝肿大和肝再生，而且还促进体内CYP3A1/2和CYP2C6/11等PXR下游代谢酶的蛋白表达和代谢活性。
