Domingo J L, Gómez M, Jones M M
Laboratory of Toxicology and Environmental Health, School of Medicine, Rovira i Virgili University, Reus, Spain.
Biol Trace Elem Res. 2000 May;74(2):127-39. doi: 10.1385/BTER:74:2:127.
D-Penicillamine (DPA) is effective in the treatment of Wilson's disease, whereas zinc salts are also used as a therapy for this disorder of copper transport. Recently, it has been shown that the copper chelators 1,4,7,11-tetraazaundecane tetrahydrochloride (TAUD) and tetraethylenepentamine pentahydrochloride (TETREN) could be useful for copper mobilization in rats. Because these agents could be potential clinical alternatives to DPA for patients with Wilson's disease who are intolerant to this drug, we examined whether oral administration of TAUD and TETREN could be effective in mobilizing copper in experimental copper-overloaded rats. The efficacy of a combined administration of zinc and DPA, TAUD, or TETREN was also assessed. Rats were copper loaded with 0.125% copper acetate in water for 12 wk. After this period, DPA, TAUD, and TETREN were administered by gavage at 0.67 mmol/kg/d for 5 d, and zinc was given at 2.5 mg Zn/kg/d. Twelve weeks of copper loading resulted in a 32-fold increase in total hepatic copper. TETREN was the most effective chelator in increasing the urinary excretion of copper. However, it did not reduce significantly the hepatic copper levels. In turn, combined administration of zinc and chelating agents significantly reduced the amount of copper found in the feces. Although TAUD and TETREN showed a similar or higher efficacy to DPA in mobilizing copper, concurrent treatment of chelating agents and zinc salts should be discarded according to the current results.
D-青霉胺（DPA）对威尔逊病的治疗有效，而锌盐也被用作这种铜转运障碍疾病的一种疗法。最近，有研究表明，铜螯合剂1,4,7,11-四氮杂十一烷四盐酸盐（TAUD）和四乙烯五胺五盐酸盐（TETREN）可能有助于大鼠体内的铜动员。由于这些药物可能是对DPA不耐受的威尔逊病患者的潜在临床替代药物，我们研究了口服TAUD和TETREN是否能有效动员实验性铜过载大鼠体内的铜。同时还评估了锌与DPA、TAUD或TETREN联合给药的疗效。给大鼠饮用含0.125%醋酸铜的水12周以使其铜负荷增加。在此期间过后，通过灌胃给予DPA、TAUD和TETREN，剂量为0.67 mmol/kg/天，持续5天，同时给予锌，剂量为2.5 mg Zn/kg/天。12周的铜负荷导致肝脏总铜含量增加了32倍。TETREN是增加尿铜排泄最有效的螯合剂。然而，它并没有显著降低肝脏铜水平。相反，锌与螯合剂联合给药显著减少了粪便中的铜含量。尽管TAUD和TETREN在动员铜方面显示出与DPA相似或更高的疗效，但根据目前的结果，应放弃螯合剂与锌盐的联合治疗。
