新型促排剂NBED对铀的促排效果及机制  

Effect and mechanism of NBED on uranium excretion

作　　者：张梦丹 周文华 龚佳格 李鹏 高洁 李建国[2] ZHANG Mengdan;ZHOU Wenhua;GONG Jiage;LI Peng;GAO Jie;LI Jianguo(School of Chinese Medicine and Food Engineering,Shanxi University of Traditional Chinese Medicine,Jinzhong 030619,China;China Institute for Radiation Protection/Shanxi Key Laboratory of Drug Toxicology and Drug for Radiation Injury/CNNC Key Laboratory on Radiotoxicology and Radiopharmaceutical Preclinical Evaluation,Taiyuan 030006,China)

机构地区：[1]山西中医药大学中药与食品工程学院,山西晋中030619 [2]中国辐射防护研究院/药物毒理与放射损伤药物山西省重点实验室/中核放射毒理与放射性药物临床前评价重点实验室,山西太原030006

出　　处：《中国药理学与毒理学杂志》2023年第12期923-927,共5页Chinese Journal of Pharmacology and Toxicology

基　　金：十三五后处理专项(HC17110217)。

摘　　要：目的研究N1,N2-双(2,3-二羟基-4,6-二磺酸苄基)亚乙基二胺钠盐(NBED)对铀的促排效果和机制。方法ICR小鼠分为正常对照组、铀染毒组、铀染毒+三乙烯三胺五乙酸钙钠盐(DTPA-CaNa_(3))150 mg·kg^(-1)组(阳性对照)、铀染毒+NBED(45,90和180 mg·kg^(-1))组。除正常对照组外,其余组小鼠尾静脉iv给予醋酸铀酰〔相当于铀(Ⅳ)0.03 mg每只〕后立即尾静脉iv给予相应剂量DTPA-CaNa_(3)或NBED,24 h后采用电感耦合等离子体质谱(ICP-MS)法测定肾、骨、肝、脾和肌肉中铀含量(肝、脾和肌肉组织合并检测)。采用电位滴定法测定NBED的解离常数及NBED与铀酰的络合常数。结果动物实验结果表明,与铀染毒组相比,铀染毒+NBED 45,90和180 mg·kg^(-1)组肾铀蓄积量降低48.2%~66.5%(P<0.01),骨降低21.4%~54.8%(P<0.01),肝+脾+肌肉降低38.2%(P<0.01),且有剂量依赖趋势;铀染毒+DTPA-CaNa_(3)组肾、骨、肝脾肌肉中铀蓄积量仅分别减少47.8%,21.4%和22.7%(P<0.05),NBED 180 mg·kg^(-1)促排效果显著优于DTPA-CaNa_(3)150 mg·kg^(-1)(P<0.05)。电位滴定实验结果表明,pH 7.4时,约有22.3%LH_(5),59.8%LH_(4)和17.85%LH_(3)(L表示NBED,H为NBED结合的H^(+)),二级解离LH_(4)为主要存在形式;pH 3~11时,NBED与铀酰存在4种络合形式,其累积形成常数分别是logβ_(111)(12.5),logβ_(101)(9.8),logβ_(102)(15.3)和logβ_(1-12)(6.5)。pH 7.4时75.3%以(UO_(2))L_(2)^(2-)的形式存在,且溶液中游离铀酰离子的-log[UO_(2)^(2+)_(free)]值,即pUO_(2)为9.57。结论NBED在体内主要以二级解离LH_(4)形式存在,与铀酰2∶1螯合为铀酰复合物排出体外,且NBED具有较好的促排效果,优于DTPA-CaNa_(3)。OBJECTIVE To study the effect and mechanism of N1,N2 bis(2,3-dihydroxy-4,6-disul⁃fonic acid benzyl)ethylenediamine sodium salt(NBED)on uranium excretion.METHODS ICR mice were divided into the blank control group,uranium exposure group(0.03 mg·mouse-1),uranium expo⁃sure+diethylenetriamine pentaacetic acid(DTPA-CaNa_(3))(150 mg·kg^(-1))group,and the uranium expo⁃sure+NBED(45,90,180 mg·kg^(-1))group.After uranyl acetate was injected into the tail vein of mice,appro⁃priate doses of NBED or DTPA-CaNa_(3)were injected into the tail vein.After 24 h,the uranium contents in the kidney,bone and liver+spleen+muscle were determined by inductively coupled plasma mass spectrometry(ICP-MS).The dissociation constant of NBED and the complexation constant of NBED with uranyl were determined via potentiometric titration.RESULTS Animal experiments showed that NBED 45,90 and 180 mg·kg^(-1)could significantly reduce the uranium accumulation in the kidney by 48.2%-66.5%,in the bone by 21.4%-54.8%,and in liver+spleen+muscle by 38.2%(P<0.01),compared to the uranium exposure group,47.8%,21.4%and 22.7%respectively by DTPA-CaNa_(3)(P<0.05),and the effect in the NBED 180 mg·kg^(-1)group was significantly better than in the DTPA-CaNa_(3)group(P<0.05).The results of potentiometric titration showed that there was about 22.3%LH_(5),59.8%LH_(4)and 17.85%LH_(3)(L means NBED)in NBED at pH 7.4,and the secondary dissociation LH_(4)was the main form.In the range of pH 3-11,there were four complex compounds of NBED and uranyl,and their step⁃wise complex cumulative constants were logβ_(111)(12.5),logβ_(101)(9.8),logβ_(102)(15.3),logβ_(1-12)(6.5)respectively.The(UO_(2))L_(2)^(2-)was the main species(75.3%)at physiological pH 7.4,and the-log[UO_(2)^(2+)_(free)]value(pUO_(2))of free uranyl ion in solution was 9.57.CONCLUSION NBED mainly exists in the form of secondary dissociated LH_(4)in vivo,and chelates with uranyl 2:1 to form uranyl complex,which is excreted in vitro.Intravenous administration of NBED can more effectively promote exc

关 键 词：促排剂 NBED 醋酸铀酰 解离常数 络合常数 

分 类 号：R96[医药卫生—药理学] R818.05[医药卫生—药学]