Role of Selenocystine in Lead Toxicity

描述(由申请人提供)：尽管为降低环境中的铅水平做出了几项努力，但铅暴露仍然是一个主要的公共卫生问题，特别是在美国的城市地区，以及在第三世界国家。铅可以通过食物、水、空气和土壤进入生物系统。1978年，含铅油漆被禁止。尽管有这项禁令，但据报道，2002年仅美国就有3800万个生活单元仍然含有含铅涂料。饮用水可能会被铅污染。市政基础设施配电系统包含铅或铜服务管道(由铅焊料连接)。最近的一项调查(2004年)估计，DC地区18%的家庭拥有含铅供水管道，30%的受试者的血铅水平超过5毫克/分升。铅中毒的传统治疗方法是使用与铅结合的螯合剂。不幸的是，目前可用的螯合剂有严重的副作用，因此许多医生不愿使用它们。铅中毒并不是使用螯合剂的唯一障碍，其他障碍包括重金属中毒(汞和镉中毒)、自闭症(认为重金属中毒可能是原因)和冠状动脉疾病(相信螯合剂可以消除钙化的动脉粥样硬化斑块)。最近的案例报告(2005年)还表明，不熟悉螯合剂的卫生保健提供者使用Na2EDTA代替CaNa2EDTA来消除儿童体内的铅。这是一个致命的错误，因为Na2EDTA会导致低血钙症，并可能导致致命的手足抽搐。因此，在铅中毒中使用像CaNa2EDTA这样的螯合剂是非常有害的，而且非常昂贵(每个儿童30,000美元)。由于铅间接地诱导自由基，我们以前对天然抗氧化剂的研究表明，对铅没有显著的螯合作用。最近，一种新设计的N-乙酰半胱氨酸酰胺形式(N-乙酰半胱氨酸酰胺，NACA)显示出良好的抗氧化/螯合作用。这种抗氧化剂和以前测试过的抗氧化剂以及已知的螯合剂的结合特性尚未被研究。因此，我们NIH(2R15 ES 09497-02)提案的这一延续将主要探索：1)NACA作为螯合剂和抗氧化剂的双重益处，以及2)螯合剂和抗氧化剂的结合常数。

DESCRIPTION (provided by applicant): Despite several efforts to reduce lead levels in the environment, lead exposure continues to be a major public health problem, particularly in urban areas in the US, as well as in third world countries. Lead can enter biological systems via food, water, air and soil. In 1978, lead-based paint was banned. Despite this ban, it was reported that 38 million living units in the US alone still contained lead-based paint in 2002. Drinking water can become contaminated by lead. Municipal infrastructure distribution systems contain lead or copper service pipes (joined by a lead solder). A recent survey (2004) estimates that 18% households in the DC area have lead service pipes and 30% of the tested people have blood lead levels greater than 5 mg/dL. Conventional treatment of lead poisoning is to use chelators that bind to lead. Unfortunately, presently available chelators have severe side effects therefore many physicians prefer not to use them. Lead poisoning is not the only disorder chelators are used, other disorders include heavy metal toxicities (mercury and cadmium toxicity), autism (in the belief that heavy metal toxicity might be the cause) and coronary artery disease (in the belief that chelators eliminate calcified atherosclerotic plaques). Recent case reports (2005) also indicated that health-care providers who are unfamiliar with chelating agents used Na2EDTA instead CaNa2EDTA to eliminate lead in children. This was a fatal mistake because Na2EDTA induces hypocalcemia and possibly fatal tetany. Therefore, use of chelators like CaNa2EDTA in lead poisoning can be very harmful and it is very costly ($30,000 per child). Because lead induces free radicals indirectly, our previous studies with natural antioxidants showed insignifivant chelation action for lead. Recently, a newly designed amide form of N-acetyl cysteine (Nacetylcysteine amide, NACA) showed promising antioxidant/chelation effects. Binding characteristics of this antioxidant and previously tested ones along with known-chelators have not been investigated. Therefore, this continuation of our NIH (2R15ES 09497-02) proposal will primarily explore: 1) the dual benefits of NACA, both as a chelator and as an antioxidant, and 2) binding constants of chelators and antioxidants.