Manipulation of Lead Using Carboxylic Acid Ionophores

描述(申请人提供)：抗生素在农业中的使用经常受到批评，因为在实践中会产生耐药菌株。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，因为抗生素离子载体被添加到几乎所有该行业雇用的物种的饲料中。更具体地说，这些化合物长期以来被认为是Na+、K+和Ca~(2+)等生理阳离子的电离团，然而，我们发现它们实际上作为Pb2+的电离团更具活性和高度选择性。由于已知这些化合物会携带到人类饮食中，因此使用离子载体作为饲料添加剂会对铅作为毒素在人类和动物中的病理生理学产生影响。这里提出的研究旨在从几个角度测试这些可能性。我们将用大鼠作为动物模型来确定，当Pb2+以典型的农业实践水平给药时，Pb2+转运离子载体会增加或减少通过肠道的铅吸收。我们还将确定Pb2+转运离子载体是否在骨骼和软组织之间以及在单个软组织之间重新分配现有的铅负荷，包括心脏、脑、肾脏、肝脏和睾丸。我们将进一步确定Pb2+转运离子载体是否改善了先前积累的铅进入循环螯合剂的途径，从而缩短了原本漫长的铅中毒螯合疗法的持续时间。我们将分别向饲料和饮用水中的大鼠投放离子载体。器官、血液、尿液和粪便中的铅含量将通过电热原子吸收光谱进行测定。离子载体水平将通过使用香草醛或荧光试剂柱后衍生化的高效液相色谱来测定。对离子载体介导的Pb2+在磷脂小泡中运输的物理化学研究以及对培养细胞中Pb2+运输的类似研究将补充这些动物研究。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。他们还可能进一步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.