Isothiocyanates reduce mercury accumulation via an Nrf2-dependent mechanism during exposure of mice to methylmercury.
Isothiocyanates reduce mercury accumulation via an Nrf2-dependent mechanism during exposure of mice to methylmercury.
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DOI：
10.1289/ehp.1003123
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发表时间：
2011-08
影响因子：
10.4
通讯作者：
Kumagai Y
中科院分区：
文献类型：
--
作者：
Toyama T;Shinkai Y;Yasutake A;Uchida K;Yamamoto M;Kumagai Y
背景：甲基汞（MeHg）通过在脑中蓄积而表现出神经毒性。转录因子Nrf 2（核因子红细胞2相关因子2）在减少甲基汞的细胞积累中起着重要作用。目的：我们研究了保护作用的异硫氰酸酯，这是已知的激活NRF 2，汞的积累后，暴露于甲基汞在体外和体内。方法：我们在体外实验中使用原代小鼠肝细胞，并将小鼠作为体内模型。我们使用了蛋白质印迹法、荧光素酶测定法、原子吸收光谱测定法和MTT [3-（4，5-二甲基噻唑-2-基）-2，5-二苯基溴化四唑]测定法，并根据后肢松弛和死亡率确定了小鼠的毒性。结果如下：异硫氰酸酯6-甲基亚磺酰基己基异硫氰酸酯（6-HITC）和莱菔硫烷（SFN）激活Nrf 2和上调下游蛋白与甲基汞排泄，如谷氨酸-半胱氨酸连接酶，谷胱甘肽S-转移酶，和多药耐药相关蛋白，在原代小鼠肝细胞。在这些条件下，细胞内谷胱甘肽水平增加野生型，但不是Nrf 2缺陷的原代小鼠肝细胞。在甲基汞暴露前用6-HITC和SFN预处理抑制了野生型但非Nrf 2缺陷原代小鼠肝细胞中汞的细胞积累和细胞毒性。相比之下，在体内给Nrf 2缺陷小鼠注射甲基汞导致对汞的敏感性增加，同时大脑和肝脏中的汞积累也增加。在注射甲基汞之前注射SFN导致野生型小鼠大脑和肝脏中汞积累减少，但Nrf 2缺陷小鼠没有。结论：6-HITC和SFN通过激活Nrf 2，可抑制甲基汞的蓄积和中毒。
Background: Methylmercury (MeHg) exhibits neurotoxicity through accumulation in the brain. The transcription factor Nrf2 (nuclear factor erythroid 2-related factor 2) plays an important role in reducing the cellular accumulation of MeHg. Objectives: We investigated the protective effect of isothiocyanates, which are known to activate Nrf2, on the accumulation of mercury after exposure to MeHg in vitro and in vivo. Methods: We used primary mouse hepatocytes in in vitro experiments and mice as an in vivo model. We used Western blotting, luciferase assays, atomic absorption spectrometry assays, and MTT [3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide] assays, and we identified toxicity in mice based on hind-limb flaccidity and mortality. Results: The isothiocyanates 6-methylsulfinylhexyl isothiocyanate (6-HITC) and sulforaphane (SFN) activated Nrf2 and up-regulated downstream proteins associated with MeHg excretion, such as glutamate-cysteine ligase, glutathione S-transferase, and multidrug resistance–associated protein, in primary mouse hepatocytes. Under these conditions, intracellular glutathione levels increased in wild-type but not Nrf2-deficient primary mouse hepatocytes. Pretreatment with 6-HITC and SFN before MeHg exposure suppressed cellular accumulation of mercury and cytotoxicity in wild-type but not Nrf2-deficient primary mouse hepatocytes. In comparison, in vivo administration of MeHg to Nrf2-deficient mice resulted in increased sensitivity to mercury concomitant with an increase in mercury accumulation in the brain and liver. Injection of SFN before administration of MeHg resulted in a decrease in mercury accumulation in the brain and liver of wild-type, but not Nrf2-deficient, mice. Conclusions: Through activation of Nrf2, 6-HITC and SFN can suppress mercury accumulation and intoxication caused by MeHg intake.
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影响因子：
5.8
作者：
FUJIYAMA, J;HIRAYAMA, K;YASUTAKE, A
通讯作者：
YASUTAKE, A
影响因子：
3.4
作者：
Kaur, Parvinder;Aschner, Michael;Syversen, Tore
通讯作者：
Syversen, Tore
影响因子：
4.8
作者：
Morimitsu, Y;Nakagawa, Y;Uchida, K
通讯作者：
Uchida, K
影响因子：
3.8
作者：
NISHIKIDO, N;FURUYASHIKI, K;IMURA, N
通讯作者：
IMURA, N
影响因子：
3.4
作者：
Rice, Deborah C.
通讯作者：
Rice, Deborah C.