INFLUENCE OF THE COMMON HUMAN DELTA-AMINOLEVULINATE DEHYDRATASE POLYMORPHISM ON LEAD BODY BURDEN
INFLUENCE OF THE COMMON HUMAN DELTA-AMINOLEVULINATE DEHYDRATASE POLYMORPHISM ON LEAD BODY BURDEN
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DOI：
10.2307/3431789
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发表时间：
1994-09-01
影响因子：
10.4
通讯作者：
WETMUR, JG
中科院分区：
文献类型：
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作者：
WETMUR, JG
β-氨基酮戊酸脱水酶(ALAD)是血红素生物合成途径中的第二个酶。ALAD是一种锌金属酶，铅替代锌对ALAD的抑制作用是最敏感的血铅蓄积指标之一，也是最近铅暴露的一个指标。化学计量学计算表明，很大一部分血铅储存在ALAD中。人类ALAD呈现电荷多态，约20%的高加索人表达罕见的ALAD(2)等位基因。人ALAD(1)和ALAD(2)的cDNA和16kb的ALAD基因已被克隆和测序。建立了一种简单的聚合酶链式反应试验，并验证了其用于ALAD基因分型。两项人群研究表明，携带ALAD(2)等位基因的铅暴露个人的血铅水平比仅携带ALAD(1)等位基因的类似暴露个人的血铅水平高约10微克/分升。目前正在进行的工作是确定血铅等位基因特异性积累的生物化学基础，以及确定人类ALAD基因对转基因小鼠模型中其他组织中铅积累的贡献以及最终在小鼠和人的骨骼中铅沉积的贡献。
delta-Aminolevulinate dehydratase (ALAD) is the second enzyme in the heme biosynthesis pathway. ALAD is a zinc metalloenzyme, and its inhibition by lead substitution for zinc is one of the most sensitive indicators of blood-lead accumulation, a measure of recent lead exposure. Stoichiometry calculations indicate that a significant portion of blood lead is stored in ALAD. Human ALAD exhibits a charge polymorphism, with about 20% of Caucasians expressing the rarer ALAD(2) allele. Human ALAD(1) and ALAD(2) cDNAs and the 16-kb ALAD gene have been cloned and sequenced. A simple polymerase chain reaction test has been established and validated for determining ALAD genotypes. Two population studies have indicated that lead-exposed individuals with the ALAD(2) allele have blood-lead levels about 10 mu g/dl greater than similarly exposed individuals carrying only the ALAD(1) allele. Ongoing work is directed toward determining the biochemistry underlying the allele-specific accumulation of blood lead, and toward determining the contribution of human ALAD genotype to lead accumulation in other tissues in transgenic mouse models and to final lead deposition in bone in both mouse and man.