Manipulation of Lead Using Carboxylic Acid Ionophores

描述（由申请人提供）：抗生素在农业中的使用经常受到批评，因为这种做法会产生耐药菌株。在抗生素离子载体的情况下，可能还有其他令人担忧的理由，这些抗生素离子载体被添加到该行业使用的几乎所有物种的饲料中。更具体地说，长期以来，人们都知道这些化合物是Na+、K+和Ca 2+等生理阳离子的离子载体，然而，我们发现它们实际上作为Pb 2+的离子载体活性更高，选择性更高。由于已知这些化合物会残留到人类饮食中，因此前景出现了使用离子载体作为饲料添加剂影响铅作为人类和动物毒素的病理生理学。这里提出的研究旨在从几个角度测试这些可能性。我们将使用大鼠作为动物模型，以确定它的Pb2+运输离子载体增加或减少铅的吸收通过肠道，当他们是典型的农业实践的水平管理。我们还将确定Pb2+转运离子载体是否重新分配骨骼和软组织之间以及个体软组织之间的现有铅负荷，包括心脏，大脑，肾脏，肝脏和睾丸。我们将进一步确定是否Pb2+转运离子载体改善之前积累的铅进入循环螯合剂，从而缩短铅中毒螯合治疗的其他漫长持续时间。我们将分别在饲料和饮用水中对大鼠施用离子载体。器官、血液、尿液和粪便中的铅含量将通过原子吸收光谱法测定。离子载体水平将通过HPLC法使用香草醛或荧光试剂进行柱后衍生测定。这些动物研究将补充磷脂囊泡中离子载体介导的Pb2+转运的物理化学研究和培养细胞中Pb2+转运的类似研究。物理化学研究强调光谱和溶液化学方法。总的来说，拟议的研究将揭示在农业中使用离子载体是否会对公众健康构成未被认识到的威胁。他们还可以确定治疗铅中毒的改进方法。

DESCRIPTION (provided by applicant): The use of antibiotics in agricultural is often criticized because resistant strains of bacteria arise from the practice. There may be additional grounds for concern in the case of antibiotic ionophores, which are added to the feed of nearly all species that are employed by this industry. More specifically, these compounds are long know to be ionophores for physiological cations such as Na+, K+, and Ca2+, however, we have found that they are actually much more active and highly selective as ionophores for Pb2+. Since the compounds are known to carryover into the human diet, the prospect arises that the use of ionophores as feed additives impacts upon the pathophysiology of lead as a toxin in humans, as well as in the animals. The studies proposed here are designed to will test those possibilities from several perspectives. We will use rats as an animal model to determine it Pb2+ transporting ionophores increase or decrease lead absorption via the gut, when they are administered at levels that are typical of agricultural practices. We will also determine if Pb2+ transporting ionophores redistribute an existing lead burden between bone and soft tissues and between individual soft tissues, including heart, brain, kidney, liver, and testis. We will furthermore determine if Pb2+ transporting ionophores improve access of previously accumulated lead to circulating chelators, and thereby shorten the otherwise lengthy duration of chelation therapy for lead intoxication. We will administer the ionophores to rats in feed and drinking water, respectively. Lead levels in organs, blood, urine and feces will be determined by electrothermal atomic absorption spectroscopy. Ionophore levels will be determined by HPLC using post-column derivatization with vanillin or fluorescent reagents. These animal studies will be complimented by a physical-chemical investigation of ionophore mediated Pb2+ transport in phospholipid vesicles and by an analogous investigation of Pb2+ transport in cultured cells. The physical-chemical studies emphasize spectroscopic and solution chemical methods. Taken in total, the proposed studies will reveal if the use of ionophores in agriculture might pose an unrecognized threat to the public health. They may furthermore identify improved methods for the treatment of lead intoxication.