Woods James S, Echeverria Diana, Heyer Nicholas J, Simmonds P Lynne, Wilkerson Jasmine, Farin Federico M
Department of Environmental and Occupational Health Sciences, University of Washington, Seattle, WA 98101, USA; Battelle Centers for Public Health Research and Evaluation, Seattle, WA 98105, USA.
Toxicol Appl Pharmacol. 2005 Aug 7;206(2):113-20. doi: 10.1016/j.taap.2004.12.016.
Previous studies have demonstrated highly specific urinary porphyrin profile (UPP) changes in response to mercury (Hg) exposure in animals and human subjects and have defined the biochemical etiology of this effect as selective alteration of the heme pathway enzymes, uroporphyrinogen decarboxylase (UROD), and coproporphyrinogen oxidase (CPOX) by Hg in the kidney. Ongoing validation studies in a population of dental practitioners with low-level occupational Hg exposure have demonstrated the predicted UPP change among approximately 85% of subjects. This study focused on the genetic etiology of an atypical porphyrinogenic response (APR) seen among the remaining 15% of Hg-exposed subjects, characterized by excess excretion of 4- and 5-carboxyl porphyrins and also of the atypical ketoisocoproporphyrin (KICP). Automated DNA-sequencing-based assays were developed to examine the 7 exons and flanking intron-exon boundaries of the CPOX gene. Among several polymorphisms identified, an A814C variant in exon 4 encoding a N272H substitution was found to be predominant among subjects with the APR. Studies suggest that this variant CPOX preferentially converts the upstream 5-carboxylporphyrin (5-CP) to KICP. By partially inhibiting the 5- to 4-decarboxylation step of UROD, Hg promotes 5-CP accumulation, accounting for e xcess KICP excretion and the APR in Hg-exposed subjects carrying the variant CPOX gene. This finding represents the first report of a polymorphism in a human gene that modifies the effect of Hg on a biological process. The APR might serve as a biomarker of both Hg exposure and susceptibility to Hg toxicity.
先前的研究已证明，动物和人类受试者在接触汞（Hg）后，尿卟啉谱（UPP）会发生高度特异性变化，并将这种效应的生化病因定义为肾脏中的汞对血红素途径酶、尿卟啉原脱羧酶（UROD）和粪卟啉原氧化酶（CPOX）的选择性改变。在低水平职业性汞暴露的牙科从业者群体中正在进行的验证研究表明，约85%的受试者出现了预测的UPP变化。本研究聚焦于其余15%汞暴露受试者中出现的非典型卟啉生成反应（APR）的遗传病因，其特征是4-羧基和5-羧基卟啉以及非典型酮异粪卟啉（KICP）排泄过量。开发了基于自动DNA测序的检测方法，以检查CPOX基因的7个外显子及其侧翼内含子-外显子边界。在鉴定出的几种多态性中，发现外显子4中编码N272H替代的A814C变体在APR受试者中占主导地位。研究表明，这种变体CPOX优先将上游的5-羧基卟啉（5-CP）转化为KICP。汞通过部分抑制UROD的5-到4-脱羧步骤，促进5-CP积累，这解释了携带变体CPOX基因的汞暴露受试者中KICP排泄过量和APR的现象。这一发现代表了人类基因多态性改变汞对生物过程影响的首次报道。APR可能作为汞暴露和汞毒性易感性的生物标志物。
