Polymorphisms in the human monomethylarsonic acid (MMAV) reductase/hGSTO1 gene and changes in urinary arsenic profiles
Polymorphisms in the human monomethylarsonic acid (MMAV) reductase/hGSTO1 gene and changes in urinary arsenic profiles
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DOI：
10.1021/tx034149a
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发表时间：
2003-12-01
影响因子：
4.1
通讯作者：
Aposhian, HV
中科院分区：
文献类型：
--
作者：
Marnell, LL;Garcia-Vargas, GG;Aposhian, HV
在人类中，慢性无机砷暴露后，尿砷谱的个体间差异很大。为了了解这种变异性，我们研究了人类甲基胂酸（MMA（V））还原酶/hGSTO 1基因多态性与长期暴露于饮用水中砷的个体尿砷谱之间的关系。为了确保我们没有忽视罕见的多态性，不包括在公共数据库中，我们扩增和测序基因的所有六个外显子及其侧翼区域，使用从75名受试者的外周血样本中分离的DNA，生活在墨西哥的托雷翁附近。根据饮用水中的砷含量（9-100 mug/L），对四组进行了研究。我们发现了六个新的多态性和两个以前报道的。新的多态性是第一内含子的三碱基对缺失（delGGC）、G > C颠换导致第86位氨基酸的丝氨酸-半胱氨酸替换、内含子5的G > T颠换和A > T颠换、G > A颠换导致第208位氨基酸的谷氨酸-赖氨酸替换、内含子5的G> C颠换导致第208位氨基酸的丝氨酸-半胱氨酸替换、内含子5的G> T颠换和A > T颠换导致第208位氨基酸的谷氨酸-赖氨酸替换。和在氨基酸236中产生丙氨酸至缬氨酸取代的C > T转变。两名受试者显示尿砷模式的显着差异，他们有增加的尿无机砷和甲基化尿砷的水平降低相比，其余的研究人群。这两个受试者在hGSTO 1中具有相同的独特多态性，因为他们是E155 del和Glu 208 Lys的杂合子。确定的SNPs可能是人类对慢性无机砷暴露的反应中存在较大个体间差异的原因之一。研究结果表明，需要进一步的研究，以确定明确的具体多态性，可能占人类对慢性无机砷暴露的反应个体间的差异。
Large interindividual variability in urinary arsenic profiles, following chronic inorganic arsenic exposure, is well-known in humans. To understand this variability, we studied the relationship between polymorphisms in the gene for human monomethylarsonic acid (MMA(V)) reductase/hGSTO1 and the urinary arsenic profiles of individuals chronically exposed to arsenic in their drinking water. To ensure that we did not overlook rare polymorphisms, not included in the public databases, we amplified and sequenced all six exons of the gene and their flanking regions, using DNA isolated from peripheral blood samples of 75 subjects, living in the vicinity of Torreon, Mexico. Four groups, based on the levels of arsenic (9-100 mug/L) in their drinking water, were studied. We identified six novel polymorphisms and two reported previously. The novel polymorphisms were a three base pair deletion (delGGC) in the first intron; a G > C transversion, leading to a serine-to-eysteine substitution at amino acid 86; a G > T transversion and a A > T transversion in intron 5; a G > A transition resulting in glutamate-to-lysine substitution in amino acid 208; and a C > T transition producing an alanine-to-valine substitution in amino acid 236. Two subjects displayed significant differences in patterns of urinary arsenic; they had increased levels of urinary inorganic arsenic and reduced levels of methylated urinary arsenic species as compared to the rest of the study population. These two subjects had the same unique polymorphisms in hGSTO1 in that they were heterozygous for E155del and Glu208Lys. The identified SNPs may be one of the reasons for the large interindividual variability in the response of humans to chronic inorganic arsenic exposure. The findings suggest the need for further studies to identify unambiguously specific polymorphisms that may account for interindividual variability in the human response to chronic inorganic arsenic exposure.