Department of Cell and Molecular Pharmacology and Experimental Therapeutics, Medical University of South Carolina, Charleston, SC 29425, USA.
Biomed Pharmacother. 2012 Sep;66(6):403-8. doi: 10.1016/j.biopha.2012.06.007. Epub 2012 Jul 2.
The ATP-binding cassette transporter 2 (ABCA2) is an endolysosomal protein expressed in oligodendrocytes and Schwann cells, prostate, ovary and macrophages. In cell cultures, ABCA2 over-expression has been linked with resistance to the anticancer agent, estramustine phosphate (EMP; a nor-nitrogen mustard conjugate of estradiol). The present study shows that Abca2 knockout (KO) mice have greater sensitivity to a variety of side effects induced by EMP treatment. Chronic EMP (12×100 mg/kg body weight) produced mortality in 36% of KO mice, but only 7% of age-matched wild type (WT). Side effects of the drug were also more prevalent in the KO mouse. For example, during the first week of EMP treatments, 67% of KO males (compared to 6% of WT males) responded with episodic erectile events. In WT mice, ABCA2 protein localized within pene corpuscles, (which rely on modified Schwann cells for amplification of tactile signals) suggesting that the transporter may function in the erectile process. Endothelial nitric oxide synthase (eNOS; a source of nitric oxide during erectile response) levels were similar in WT and KO male penile tissue. Treatment with 100 mg/kg EMP (once daily for four days) elevated serum estradiol and estrone in both WT and KO. However, the circulating levels of these estrogens were higher in KO mice implying a reduced plasma clearance of estrogens as a consequence of ABCA2 ablation. Consistent with the pro-convulsant effects of estrogens, KO mice also displayed an increased incidence of seizures following EMP (14% vs. 0%). Taken together, these data indicate that ABCA2 deficiency renders mice more sensitive to EMP treatment-induced effects implying that the transporter has a role in regulating EMP transport and/or metabolism.
三磷酸腺苷结合盒转运体 2（ABCA2）是一种在少突胶质细胞和施万细胞、前列腺、卵巢和巨噬细胞中表达的内溶酶体蛋白。在细胞培养中，ABCA2 的过度表达与对抗癌药物磷酸雌莫司汀（EMP；雌二醇的氮芥类似物）的耐药性有关。本研究表明，ABCA2 敲除（KO）小鼠对 EMP 治疗引起的多种副作用更敏感。慢性 EMP（12×100mg/kg 体重）导致 36%的 KO 小鼠死亡，但只有 7%的同龄野生型（WT）小鼠死亡。药物的副作用在 KO 小鼠中也更为常见。例如，在 EMP 治疗的第一周，67%的 KO 雄性（相比之下，WT 雄性为 6%）出现间歇性勃起事件。在 WT 小鼠中，ABCA2 蛋白定位于阴茎体（其依赖于改良的施万细胞来放大触觉信号），这表明该转运蛋白可能在勃起过程中发挥作用。内皮型一氧化氮合酶（eNOS；勃起反应期间一氧化氮的来源）在 WT 和 KO 雄性阴茎组织中的水平相似。用 100mg/kg EMP（每天一次，连续四天）处理后，WT 和 KO 小鼠的血清雌二醇和雌酮水平均升高。然而，KO 小鼠的这些雌激素循环水平更高，这意味着 ABCA2 缺失导致雌激素的血浆清除率降低。与雌激素的促惊厥作用一致，KO 小鼠在 EMP 治疗后（14%对 0%）也显示出更高的癫痫发作发生率。综上所述，这些数据表明 ABCA2 缺乏使小鼠对 EMP 治疗诱导的作用更敏感，这表明该转运蛋白在调节 EMP 转运和/或代谢中起作用。
