LEAD TOXICITY AND THE ALA-DEHYDRATASE POLYMORPHISM

δ-氨基酮戊酸脱水酶（ALAD，EC 4.2.1.4）是一种锌 一种金属酶，铅对它的抑制作用是第一个也是最敏感的 铅暴露的指标，其活动的减少已被明确 与铅中毒的发病机制有关。 这种酶由 ALAD 1（p = 0.9）和ALAD 2（q = 0.1）两个等位基因。 一个分子测试， ALAD基因分型是基于ALAD 1的DNA序列开发的。 和ALAD 2等位基因。 我们实验室的证据表明铅- ALAD 2杂合子或纯合子暴露个体的平均血 铅含量比类似暴露的个体高9微克/分升 ALAD 1纯合子。 这些结果表明，在基因上 易受感染的个体，如果暴露于 在工作场所或环境中发挥领导作用。 此外，由于铅是已知的 致畸剂，具有这种遗传易感性的女性的胎儿可能会 铅导致先天性畸形的风险更高。 在这 我们提出三项研究： 首先，研究ALAD等位基因与铅的关系， 中毒将扩大到包括铅暴露的综合措施。 血铅是铅暴露的一种急性指标， 最终保留的铅量。 铅暴露人群ALAD基因型 人口也将与骨或乳牙牙本质铅 水平，两者都是铅暴露的综合措施。 其次，将研究小鼠模型以关联（a）小鼠ALAD活性 和/或浓度，导致在身体组织中的保留和分布，或 (b)人ALAD活性和/或浓度对铅滞留的影响， 在组织中的分布 这些模型将涉及铅暴露（a） 具有不同ALAD基因剂量的现有小鼠品系以及（B） 表达人ALAD 1或ALAD 2等位基因的转基因小鼠。 铅摄入量， 铅的组织特异性分布与组织ALAD的抑制 将由牵头确定，以进一步阐明ALAD在以下方面的作用： 铅中毒的病理生理学 最后，纯化的重组人ALAD同工酶将用于确定 它们对铅结合的不同亲和力，铅的抑制作用， 蛋白酶抑制 还将提供重组同工酶 用于X射线测定其晶体结构。 这些研究 旨在确定差异遗传的生化基础， 个体对铅暴露的敏感性。

Delta-aminolevulinic acid dehydratase (ALAD, EC 4.2.1.4) is a zinc metalloenzyme whose inhibition by lead is the first and most sensitive indicator of lead exposure and whose decreased activity has been clearly implicated in the pathogenesis of lead poisoning. The enzyme is encoded by two alleles, ALAD1 (p = 0.9) and ALAD2 (q = 0.1). A molecular test for ALAD genotyping has been developed based on the DNA sequences of the ALAD1 and ALAD 2 alleles. Evidence from our laboratory indicates that lead- exposed individuals heterozygous or homozygous for ALAD 2 have mean blood lead levels 9 micrograms/dl greater than similarly exposed individuals homozygous for ALAD1. These results suggest that there are genetically susceptible individuals who would be at an increased health risk if exposed to lead in the workplace or environment. Moreover, since lead is a known teratogen, the fetuses of women with such a genetic susceptibility may be at higher risk for lead-induced congenital abnormalities. In this application we propose three studies: First, investigation of the relationship of the ALAD alleles to lead poisoning will be extended to include integrated measures of lead exposure. Blood lead is an acute measure of lead exposure and does not measure the amount of lead ultimately retained. ALAD genotypes in lead-exposed populations will also be related to bone or deciduous teeth dentine lead levels, both integrated measures of lead exposure. Second, mouse models will be investigated to relate (a) mouse ALAD activity and/or concentration to lead retention and distribution in body tissues or (b) human ALAD activity and/or concentration to lead retention and distribution in tissues. These models will involve lead exposure of (a) existing mouse strains with differing ALAD gene doses as well as (b) transgenic mice expressing the human ALAD1 or ALAD2 allele. Lead uptake, the tissue-specific distribution of lead and the inhibition of tissue ALAD by lead will be determined in order to clarify further the role of ALAD in the pathophysiology of lead poisoning. Finally, purified recombinant human ALAD isozymes will be used to determine their differential affinity for lead binding, inhibition by lead, and protease inhibition. The recombinant isozymes will also be made available for X-ray determination of their crystal structures. These studies are aimed at determining the biochemical basis for the differential genetic susceptibility of individuals to lead exposure.