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c-Myc反义核酸限制大鼠肝脏再生,并表明c-Myc在调节细胞色素P-450 3A活性中的作用。

c-Myc antisense limits rat liver regeneration and indicates role for c-Myc in regulating cytochrome P-450 3A activity.

作者信息

Arora V, Knapp D C, Smith B L, Statdfield M L, Stein D A, Reddy M T, Weller D D, Iversen P L

机构信息

AVI BioPharma, Corvallis, Oregon, USA.

出版信息

J Pharmacol Exp Ther. 2000 Mar;292(3):921-8.

Abstract

Expression of c-myc protein is associated with cell proliferation. The present study uses antisense oligomers to inhibit c-myc expression in the regenerating rat liver after 70% partial hepatectomy (PH). Antisense phosphorodiamidate morpholino oligomers (novel DNA analogs) were administered i.p. immediately after surgery to block expression of c-myc within the first 24 h after PH. A 20-mer PMO complimentary to the c-myc mRNA at the translation start site was an effective sequence (AVI-4126, 5'-ACGTTGAGGGGCATCGTCGC-3'). A single i.p. dose of 0.5 mg/kg AVI-4126 caused reduction of the regenerating liver c-myc protein in a sequence-specific and dose-dependent manner. Inhibition of c-myc expression resulted in reduction of proliferating cell nuclear antigen and arrested cells in the G(0)/G(1) phase of the cell cycle. The ratio of G(2):G(0) cell populations in the regenerating liver 24 h after PH dropped from 29.1 in saline vehicle-treated rats to 18.0 in rats treated with 2.5 mg/kg AVI-4126. The expression of cell cycle checkpoint protein p53 was inhibited with increasing doses of AVI-4126, but expression of p21(waf-1) was unaffected. The activity of cytochrome P-450 3A2 (CYP3A2) was evaluated by immunoblot analysis and erythromycin N-demethylation. AVI-4126 did not alter CYP3A activity in nonhepatectamized animals but showed a dose-dependent decrease in PH rats. We conclude that AVI-4126, antisense oligomer to c-myc, can reduce cell proliferation in the regenerating rat liver. Furthermore, inhibition of c-myc may indirectly influence the expression of CYP3A.

摘要

c-myc蛋白的表达与细胞增殖相关。本研究采用反义寡聚体抑制大鼠70%肝部分切除术后再生肝中c-myc的表达。反义磷酰二胺吗啉代寡聚体(新型DNA类似物)在手术后立即腹腔注射,以在肝部分切除术后的头24小时内阻断c-myc的表达。在翻译起始位点与c-myc mRNA互补的20聚体PMO是有效的序列(AVI-4126,5'-ACGTTGAGGGGCATCGTCGC-3')。单次腹腔注射0.5mg/kg AVI-4126能以序列特异性和剂量依赖性方式降低再生肝中的c-myc蛋白。c-myc表达的抑制导致增殖细胞核抗原减少,细胞周期停滞在G(0)/G(1)期。肝部分切除术后24小时再生肝中G(2):G(0)细胞群体的比例从生理盐水处理大鼠的29.1降至2.5mg/kg AVI-4126处理大鼠的18.0。随着AVI-4126剂量增加,细胞周期检查点蛋白p53的表达受到抑制,但p21(waf-1)的表达未受影响。通过免疫印迹分析和红霉素N-脱甲基化评估细胞色素P-450 3A2(CYP3A2)的活性。AVI-4126在未行肝部分切除的动物中未改变CYP3A活性,但在肝部分切除大鼠中呈剂量依赖性降低。我们得出结论,c-myc的反义寡聚体AVI-4126可减少大鼠再生肝中的细胞增殖。此外,c-myc的抑制可能间接影响CYP3A的表达。

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