全反式维A酸给药4周对大鼠的毒性作用  

Toxicity of all-trans retinoic acid for four-week oral administration in SD rats

作　　者：陈雁虹[1] 盖仁华[2] 吴洪海[2] 

机构地区：[1]浙江大学实验动物中心,浙江杭州310058 [2]浙江大学药物安全评价研究中心,浙江杭州310058

出　　处：《中国药理学与毒理学杂志》2013年第2期248-255,共8页Chinese Journal of Pharmacology and Toxicology

摘　　要：目的观察全反式维A酸(ATRA)重复给药4周对大鼠的毒性反应,初步确定其主要毒性靶器官及毒性反应性质和程度。方法 SD大鼠ig给予ATRA 10,50和250 mg.kg-1,每日1次,连续4周,每日观察大鼠的一般状况和死亡情况,每周记录体质量和摄食量。停药第1天和第15天分别处死部分大鼠,进行血常规、血液生化和凝血功能检测,测定主要脏器的脏器系数并进行常规病理组织学检查。结果 与溶剂对照组相比,ATRA 250 mg.kg-1组给药14 d后,大鼠出现竖毛、自主活动减少、四肢乏力、眼睑部脱毛出血和呼吸急促等症状,给药18 d后大鼠出现死亡,体质量在给药7 d后随给药时间延长逐渐减轻(P<0.01),同时摄食量随给药时间延长逐渐减少(P<0.05)。停药后第1天,与溶剂对照组比较,ATRA250 mg.kg-1组总蛋白、白蛋白、总胆红素和肌酐明显下降,球蛋白、丙氨酸转氨酶、天冬氨酸转氨酶和甘油三酯明显上升(P<0.01),同时血糖升高,肌酸肌酶显著降低(P<0.05);中性粒细胞、单核细胞和网织红细胞明显增加,嗜酸性粒细胞、红细胞、血红蛋白浓度、红细胞压积和血小板数明显降低(P<0.01);血浆凝血酶原时间和国际标准化比值明显延长,凝血酶时间明显减少(P<0.05);心、肝、脾、肺、肾和肾上腺系数较溶剂对照组明显升高,胸腺系数明显降低(P<0.01)。ATRA组组织病理改变主要为肝细胞水肿,十二指肠上皮变性、坏死,脾巨核细胞增多。停药后第15天,ATRA组的毒性反应症状有所恢复。结论 ATRA250 mg.kg-1能造成大鼠血小板减少和贫血,同时存在一定的粒系增生和骨髓抑制现象,对大鼠肝和生殖系统有损伤。OBJECTIVE To investigate the four-week oral toxicity of all-trans retinoic acid （ATRA） in SD rats and to confirm the mainly toxic target organs, character and degree of toxicological effects. METHODS SD rats were ig given ATRA 10, 50 and 250 mg·kg-1, once daily, for 4 weeks. The gen eral state and death of rats were observed daily, and the body mass and food intake were recorded weekly. Rats were sacrificed on either the lst（ d 1 ） or d 15 after drug withdrawal. Blood biochemistry and coagulation parmeters were measured. The major organ indexes were determined and histopatholo- gy was detected. RESULTS Rats in ATRA 250 mg.kg-1 group showed symptoms of erect hair, decreased activities, limb weakness, epilation and bleed of eyelid and shortness of breath after adminis- tration for 2 weeks. Compared with solvent control group, death occurred on d 18, and the gradual decrease of body mass loss and food intake was statisticall significance（ P〈0.05）. On d 1 after drug withdrawal, compared with solvent control group, the total protein, albumin, total bilirubin, and creati- nine levels markedly decreased in ATRA 250 mg.kg-1 group （P 〈 0.01 ） while the globulin, alanine transaminase, alkaline phosphatase, and triglycerides levels markedly increased （ P 〈 0.01 ）, accompa- nied by rising glucose（ P 〈 0.05） and decreasing creatine kinase （P〈0.05）. There was significant difference（P 〈 0.01 ） in the blood parameters between ATRA 250 mg·kg-1 group and solvent control group except the white blood cell count, lymphocyte and basophil. Compared with solvent control group, prothrombin time and international normalized ratio in ATRA 250 mg.kg-1 group obviously increased while thrombin time was significantly decreased（ P 〈 0.05）. The organ indexes of the heart, liver, spleen, lung, kidney and adrenal were significantly increased while thymic organ indexes significantly decreased （ P 〈0.01 ）. The histopathological changes in ATRA groups included liver cell edema, duodenal epithe

关 键 词：维A酸 毒性实验 药物毒性 

分 类 号：R965[医药卫生—药理学]