Disruption of the arsenic (+3 oxidation state) methyltransferase gene in the mouse alters the phenotype for methylation of arsenic and affects distribution and retention of orally administered arsenate.
Disruption of the arsenic (+3 oxidation state) methyltransferase gene in the mouse alters the phenotype for methylation of arsenic and affects distribution and retention of orally administered arsenate.
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DOI：
10.1021/tx900179r
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发表时间：
2009-10
影响因子：
4.1
通讯作者：
Thomas, David J.
中科院分区：
文献类型：
--
作者：
Drobna, Zuzana;Naranmandura, Hua;Kubachka, Kevin M.;Edwards, Brenda C.;Herbin-Davis, Karen;Styblo, Miroslav;Chris Le, X.;Creed, John T.;Maeda, Noboyu;Hughes, Michael F.;Thomas, David J.
砷(+3氧化态)甲基转移酶(AS3MT)基因编码一个43 kDa的蛋白质，催化无机砷的甲基化。在培养的人类细胞中，AS3MT的表达变化控制着砷的甲基化表型，这表明在砷的代谢中起着关键作用。由于甲基化的砷化合物介导了一些与无机砷暴露有关的毒性或致癌效应，因此研究砷化合物在不能甲基化砷的小鼠身上的命运和影响可能是有指导意义的。本研究比较了AS3MT基因敲除小鼠和AS3MT基因表达正常的野生型C57BL/6小鼠体内砷的滞留和分布。每公斤含[73As]-砷的雄性和雌性小鼠口服剂量为0.5毫克的砷。给药后对小鼠进行长达96小时的放射检测；在给药后2小时和24小时收集组织。在给药后2小时和24小时，AS3MT基因敲除小鼠的肝脏中无机砷和单甲基化砷的比例高于C57BL/6小鼠的肝脏。在AS3MT基因敲除者的尿液中也发现了类似的无机砷和单甲基化砷的优势。在给药24小时后，AS3MT基因敲除小鼠在肝脏、肾脏、膀胱、肺、心脏和身体中保持的砷剂量百分比显著高于C57BL/6小鼠。在AS3MT基因敲除的小鼠中，[73As]的全身清除明显慢于C57BL/6小鼠。在给药24小时后，AS3MT基因敲除小鼠保留了约50%的剂量，C57BL/6小鼠保留了约6%的剂量。96小时后，AS3MT基因敲除保留了约20%，C57BL/6小鼠保留了不到2%的剂量。这些数据证实了AS3MT在无机砷代谢中的中心作用，并表明砷的保留和分布的表型明显受砷甲基化零基因的影响，表明砷的代谢和保留之间存在密切的联系。
The arsenic (+3 oxidation state) methyltransferase (As3mt) gene encodes a 43 kDa protein that catalyzes methylation of inorganic arsenic. Altered expression of AS3MT in cultured human cells controls arsenic methylation phenotypes, suggesting a critical role in arsenic metabolism. Because methylated arsenicals mediate some toxic or carcinogenic effects linked to inorganic arsenic exposure, studies of the fate and effects of arsenicals in mice which cannot methylate arsenic could be instructive. This study compared retention and distribution of arsenic in As3mt knockout mice and in wild-type C57BL/6 mice in which expression of the As3mt gene is normal. Male and female mice of either genotype received an oral dose of 0.5 mg of arsenic as arsenate per kg containing [73As]-arsenate. Mice were radioassayed for up to 96 hours after dosing; tissues were collected at 2 and 24 hours after dosing. At 2 and 24 hours after dosing, livers of As3mt knockouts contained a greater proportion of inorganic and monomethylated arsenic than did livers of C57BL/6 mice. A similar predominance of inorganic and monomethylated arsenic was found in the urine of As3mt knockouts. At 24 hours after dosing, As3mt knockouts retained significantly higher percentages of arsenic dose in liver, kidneys, urinary bladder, lungs, heart, and carcass than did C57BL/6 mice. Whole body clearance of [73As] in As3mt knockouts was substantially slower than in C57BL/6 mice. At 24 hours after dosing, As3mt knockouts retained about 50% and C57BL/6 mice about 6% of the dose. After 96 hours, As3mt knockouts retained about 20% and C57BL/6 mice retained less than 2% of the dose. These data confirm a central role for As3mt in metabolism of inorganic arsenic and indicate that phenotypes for arsenic retention and distribution are markedly affected by the null genotype for arsenic methylation, indicating a close linkage between the metabolism and retention of arsenicals.
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影响因子：
5.1
作者：
MARAFANTE, E;VAHTER, M;ENVALL, J
通讯作者：
ENVALL, J
影响因子：
4.5
作者：
Liu, J;Liu, YP;Klaassen, CD
通讯作者：
Klaassen, CD
影响因子：
4.1
作者：
Naranmandura, Hua;Suzuki, Noriyuki;Suzuki, Kazuo T.
通讯作者：
Suzuki, Kazuo T.
DOI：
10.1007/s004200050248
发表时间：
1998-02-01
影响因子：
3
作者：
Concha, G;Vogler, G;Vahter, M
通讯作者：
Vahter, M
影响因子：
4.5
作者：
Csanaky, I;Gregus, Z
通讯作者：
Gregus, Z