Background

Nuclear receptor are major regulators of hepatic drug metabolizing enzymes and antioxidants enzymes. Nuclear receptor humanized mice were used for overcome species differences between experimental animals and human.

Objective

The present study was performed to investigate the hepatic regulation of antioxidant enzymes in pregnane X receptor (PXR) and constitutive androstane receptor (CAR) double humanized mice treated with the human PXR ligand, rifampicin (RIF; 10 mg/kg for 4 days).

Results

RIF decreased the hepatic protein levels of superoxide dismutase-1, thioredoxin-1, and γ-glutamylcysteine ligase catalytic subunit in wild-type (WT) mice, but not in the double humanized mice. Catalase protein levels were decreased by RIF in both WT and double humanized mice. The hepatic protein level and activity of glutathione reductase (GR) were increased in the humanized mice treated with RIF, but decreased in WT mice. Glutathione S-transferase (GST) alpha-class (GSTA) and mu-class (GSTM) but not pi-class were induced by RIF in the humanized mice, but not in WT mice. The activities of total GST, GSTA and GSTM were also increased only in humanized mice treated with RIF.

Conclusion

These results suggest that PXR and CAR may play roles in xenobiotic-induced hepatic regulation of GSTA, GSTM, and GR. The PXR/CAR double humanized mouse can be used as a suitable predictive model of the regulation of human antioxidant enzymes by xenobiotics.

中文翻译：

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利福平对PXR和CAR双重人源化小鼠肝抗氧化酶的影响

背景

核受体是肝药物代谢酶和抗氧化剂酶的主要调节剂。核受体人源化小鼠用于克服实验动物与人之间的物种差异。

客观的

进行本研究以研究用人PXR配体利福平（RIF; 10 mg / kg连续4天）治疗的孕烷X受体（PXR）和组成型雄激素受体（CAR）双重人源化小鼠中抗氧化酶的肝脏调节作用。

结果

RIF降低了野生型（WT）小鼠中超氧化物歧化酶-1，硫氧还蛋白1和γ-谷氨酰半胱氨酸连接酶催化亚基的肝蛋白水平，但在双重人源化小鼠中却没有。在野生型和双重人源化小鼠中，RIF均可降低过氧化氢酶蛋白水平。用RIF处理的人源化小鼠肝蛋白水平和谷胱甘肽还原酶（GR）活性增加，而WT小鼠则降低。谷胱甘肽S-转移酶（GST）α级（GSTA）和mu级（GSTM），但不是pi级，是通过RIF在人源化小鼠中诱导的，而不是在WT小鼠中诱导的。总GST，GSTA和GSTM的活性也仅在用RIF治疗的人源化小鼠中增加。

结论

这些结果表明，PXR和CAR可能在异源生物诱导的GSTA，GSTM和GR的肝脏调节中发挥作用。PXR / CAR双重人源化小鼠可用作异种生物调节人抗氧化酶的合适预测模型。