Hernández Alba, Xamena Noel, Surrallés Jordi, Sekaran Chandra, Tokunaga Hiroshi, Quinteros Domingo, Creus Amadeu, Marcos Ricardo
Grup de Mutagènesi, Departament de Genètica i de Microbiologia, Universitat Autònoma de Barcelona, Bellaterra, Spain.
Mutat Res. 2008 Jan 1;637(1-2):80-92. doi: 10.1016/j.mrfmmm.2007.07.004. Epub 2007 Jul 22.
Chronic exposure to arsenic involves a biotransformation process leading to the excretion of methylated metabolites, such as monomethylarsonic acid (MMA) and dimethylarsinic acid (DMA), as well as the parental inorganic species (As(III) and As(V)). Inter-individual variations in arsenic biotransformation have been reported and polymorphisms affecting the genes involved in arsenic biotransformation have been considered as one of the plausible explanations for this variation. Coding and flanking regions of the human arsenic methyltransferase (AS3MT) gene have been analysed in 50 Chilean men exposed to arsenic. Nine polymorphisms were found, including one non-synonymous SNP at exon 9 (Met(287)Thr) with an allele frequency of 0.14. Other four changes occurred at potentially regulatory regions: a variable number of tandem repeats (VNTR) at the 5'-untranslated region (UTR5'), a G/C substitution at the promoter region, a GC/AT substitution inside the VNTR, and a G/A substitution at the 3'-untranslated region (UTR3'). The rest of polymorphisms were located in non-coding regions: a T/G substitution in intron 1, a CTC deletion in intron 2 and a TTT and ATT insertions in intron 5. In addition, the individual urinary arsenic profiles were analysed. Our results indicate that genetic polymorphisms in AS3MT contribute to inter-individual variation in arsenic biotransformation and, therefore, may contribute to inter-individual variations in risk of arsenic toxicity and arsenic carcinogenesis. Individuals with the Met(287)Thr polymorphism displayed increased arsenic methylation and might be at increased risk for toxic and genotoxic effects of arsenic exposure if, as the classical arsenic metabolic pathway indicates, methylation enhances toxicity.
长期接触砷会涉及一个生物转化过程，该过程会导致甲基化代谢产物的排泄，如一甲基胂酸（MMA）和二甲基胂酸（DMA），以及母体无机砷物种（As(III)和As(V)）。已有报道称砷生物转化存在个体差异，影响砷生物转化相关基因的多态性被认为是造成这种差异的一种合理原因。对50名接触砷的智利男性的人类砷甲基转移酶（AS3MT）基因的编码区和侧翼区进行了分析。发现了9种多态性，包括外显子9处的一个非同义单核苷酸多态性（Met(287)Thr），其等位基因频率为0.14。其他4种变化发生在潜在的调控区域：5'-非翻译区（UTR5'）的可变串联重复序列（VNTR）、启动子区域的G/C替换、VNTR内部的GC/AT替换以及3'-非翻译区（UTR3'）的G/A替换。其余的多态性位于非编码区：内含子1中的T/G替换、内含子2中的CTC缺失以及内含子5中的TTT和ATT插入。此外，还分析了个体的尿砷谱。我们的结果表明，AS3MT基因中的遗传多态性导致了砷生物转化的个体差异，因此可能导致砷毒性和砷致癌风险的个体差异。具有Met(287)Thr多态性的个体表现出砷甲基化增加，如果正如经典的砷代谢途径所示，甲基化会增强毒性，那么这些个体可能面临更高的砷暴露毒性和基因毒性效应风险。
