Altered ethylbenzene-mediated hepatic CYP2E1 expression in growth hormone-deficient dwarf rats.
Altered ethylbenzene-mediated hepatic CYP2E1 expression in growth hormone-deficient dwarf rats.
复制标题
改变生长激素缺乏的侏儒大鼠中乙苯介导的肝脏 CYP2E1 表达。
DOI：
10.1006/taap.2002.9349
复制
发表时间：
2002
影响因子：
3.8
通讯作者：
Backes,WayneL
中科院分区：
文献类型：
--
作者：
Zhang,Shuxin;Cawley,GeorgeF;Eyer,CharlesS;Backes,WayneL
乙苯（EB）可有效诱导几种肝P450酶，包括CYP 2 E1和CYP 2B。垂体切除减少EB介导的CYP 2B诱导的幅度。虽然生长激素（GH）在CYP 2C 11的两性异形中起着关键作用，但其对EB介导的P450表达的影响仍不清楚。由于垂体切除术会导致除GH外的多种垂体激素耗竭，因此设计了一项研究，以GH缺陷型侏儒大鼠作为更特异的动物模型，研究GH可能参与EB介导的肝脏P450表达。在这些大鼠中，垂体GH被选择性地降低至正常水平的约10%，其他垂体促激素包括促甲状腺激素、促肾上腺皮质激素、促黄体激素、促卵泡激素和催乳素基本不变。对雄性对照和HsdOla：DWARF-dw-4（哈兰，英国）大鼠进行单次ip注射EB（10 mmol/kg）。10和24小时后测量CYP 2 E1和CYP 2B依赖性活性、蛋白质和RNA水平。结果表明，未暴露于EB的侏儒大鼠表达较高的CYP 2 E1。虽然EB治疗诱导CYP 2 E1活性，蛋白质和mRNA在对照组和侏儒大鼠，EB暴露的反应的幅度更大，治疗后10小时在侏儒大鼠。与完整大鼠相比，垂体切除术也增加了EB对CYP 2 E1蛋白的诱导。这种作用被逆转GH补充垂体切除大鼠。总体而言，CYP 2B的反应，EB暴露在侏儒大鼠没有显示基本的差异，从控制。总之，结果表明：（1）在多激素缺乏型HX大鼠中发现的CYP 2B诱导抑制在更特异性的GH缺乏型大鼠模型中未发现，证实GH对CYP 2B表达无重大影响;（2）垂体切除和GH缺乏型大鼠均显示EB处理后CYP 2 E1诱导改变。
Ethylbenzene (EB) effectively induces several hepatic P450 enzymes including CYP2E1 and CYP2B. Hypophysectomy diminishes the magnitude of EB-mediated induction of CYP2B. Although growth hormone (GH) plays a key role in sexual dimorphism of CYP2C11, its impact on EB-mediated P450 expression is still unknown. Because hypophysectomy leads to a depletion of multiple pituitary hormones besides GH, a study was designed to investigate the possible involvement of GH in EB-mediated hepatic P450 expression using GH-deficient dwarf rats as a more specific animal model. In these rats, pituitary GH was selectively reduced to about 10% of normal levels and other pituitary trophic hormones including thyroid-stimulating hormone, adrenocorticotropic hormone, luteinizing hormone, follicle-stimulating hormone, and prolactin are largely unchanged. Male control and HsdOla:DWARF-dw-4 (Harlan, UK) rats were subjected to a single ip injection of EB (10 mmol/kg). CYP2E1- and CYP2B-dependent activities, protein, and RNA levels were measured 10 and 24 h afterward. The results indicated that dwarf rats without EB exposure expressed higher CYP2E1. Although EB treatment induced CYP2E1 activity, protein, and mRNA both in controls and dwarf rats, the magnitude of the response to EB exposure was greater 10 h after the treatment in dwarf rats. Hypophysectomy also increased CYP2E1 protein induction by EB compared to intact rats. This effect was reversed by GH supplementation to hypophysectomized rats. Overall, responses of CYP2B to EB exposure in dwarf rats did not display basic differences from controls. In conclusion, the results demonstrate that (1) the suppression of CYP2B induction found in the multi-hormone-deficient HX rats is not found in the more specific GH-deficient rat model, confirming that GH does not have a major influence on CYP2B expression and (2) both hypophysectomized and GH-deficient rats show an altered inducibility of CYP2E1 after EB treatment.