Chronic exposure to methylated arsenicals stimulates arsenic excretion pathways and induces arsenic tolerance in rat liver cells
Chronic exposure to methylated arsenicals stimulates arsenic excretion pathways and induces arsenic tolerance in rat liver cells
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DOI：
10.1093/toxsci/kfj117
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发表时间：
2006-05-01
影响因子：
3.8
通讯作者：
Sakurai, T
中科院分区：
文献类型：
--
作者：
Kojima, C;Qu, W;Sakurai, T
尽管无机砷对人体具有毒性和致癌性，但无机亚砷酸盐最近已成为急性早幼粒细胞白血病（APL）的一种高效化疗药物。在哺乳动物中，无机砷被酶甲基化成一甲基拉森酸（MMAsV）、二甲基拉森酸（DMAsV）和氧化三甲基拉森酸（(TMAsO)-O-V）。我们利用大鼠正常肝脏TRL 1215细胞研究了长期暴露于甲基化砷对砷耐受性的影响。TRL 1215细胞暴露于MMAsV， DMAsV或(TMAsO)-O-V中20周，产生亚微摩尔细胞浓度的砷。在长期暴露于这些甲基化砷时，细胞获得了对急性砷细胞死亡的耐受性。与传代匹配的对照细胞相比，这些细胞的细胞砷摄取减少。长期砷暴露增加谷胱甘肽s转移酶（GST）活性和细胞谷胱甘肽（GSH）水平。谷胱甘肽s -转移酶、多药耐药相关蛋白（Mrps； Mrp基因编码的外排转运蛋白）和p -糖蛋白[P-gp；多药耐药基因（MDR）编码的外排转运蛋白在这些细胞中的转录物和蛋白水平也有所增加。细胞GSH的消耗和Mrps和P-gp功能的抑制增加了细胞对砷的吸收，降低了这些细胞对砷的耐受性。这些结果表明，长期暴露于甲基化砷可引起砷排泄增加引起的普遍砷耐受性。由于慢性砷中毒患者和砷治疗的APL患者可能会发生甲基化砷的积累，本研究可能为慢性砷中毒和使用无机亚砷酸盐治疗APL产生多药耐药的潜在风险提供重要信息。
Although inorganic arsenicals are toxic and carcinogenic in humans, inorganic arsenite has recently emerged as a highly effective chemotherapeutic agent for acute promyelocytic leukemia (APL). Inorganic arsenicals are enzymatically methylated to monomethylarsonic acid (MMAsV), dimethylarsinic acid (DMAsV), and trimethylarsine oxide ((TMAsO)-O-V) in mammals. We examined the effects of chronic exposure to methylated arsenicals on arsenic tolerance by using rat normal liver TRL 1215 cells. TRL 1215 cells were exposed for 20 weeks to MMAsV, DMAsV, or (TMAsO)-O-V at levels that produced submicromolar cellular concentrations of arsenic. On chronic exposure to these methylated arsenicals, the cells acquired tolerance to acute arsenic cytolethality. Cellular arsenic uptake was reduced in these cells compared to passage-matched control cells. The long-term arsenic exposure increased glutathione S-transferase (GST) activity and cellular glutathione (GSH) levels. Glutathione S-transferase, multidrug resistance-associated proteins (Mrps; efflux transporters encoded by Mrp genes), and P-glycoprotein [P-gp; efflux transporter encoded by multidrug resistance gene (MDR)] had also increased in these cells at the transcript and protein levels. The depletion of cellular GSH and the inhibition of Mrps and P-gp functions increased cellular arsenic uptake and reduced arsenic tolerance in these cells. These results indicate that chronic exposure to methylated arsenicals induces a generalized arsenic tolerance that is caused by increased arsenic excretion. Because accumulation of methylated arsenicals may occur in patients with chronic arsenic poisoning and arsenic-treated APL patients, this study may provide important information regarding chronic arsenic poisoning and the latent risk of developing multidrug resistance in APL therapy using inorganic arsenite.