外源性Met对砷暴露小鼠体内砷甲基代谢和脑Glu及NO代谢影响的研究
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摘要
前言
地方性饮水型砷中毒是我国主要的地方病之一。水砷是人群砷暴露的主要摄入途径,饮水中的砷形态主要是无机砷(inorganic arsenic,iAs)。iAs进入体内后,经过二次氧化甲基化和二次的还原过程,最终被催化生成五价二甲基砷(Dimethylarsinic acid,DMA~(5+))。S-腺苷甲硫氨酸(S-adenosyl-L-methionine,SAM)作为甲基供体,在砷的甲基化代谢中起重要作用,而蛋氨酸(Methionine,Met)在S-腺苷甲硫氨酸合酶的作用下可以被ATP激活生成SAM。
谷氨酸(Glutamate,Glu)是中枢神经系统中兴奋性突触传递的主要神经递质,谷氨酰胺合成酶(Glutamine synthetase,GS)是Glu代谢的关键酶。一氧化氮(Nitricoxide,NO)是中枢神经系统中的重要信使分子和神经递质,由一氧化氮合酶(Nitricoxide synthase,NOS)催化L-精氨酸产生。我们前期的研究结果显示,亚慢性砷暴露可引起小鼠脑组织Glu和NO代谢的异常。
本研究拟通过给予饮水砷暴露小鼠不同剂量的外源性Met,探讨Met对小鼠各组织器官中砷形态的影响,进而探讨Met对改善砷在不同组织中毒性作用的影响,为指导饮水型地方性砷中毒的防治工作提供实验依据。
对象和方法
1、实验动物与染毒
雌性健康昆明种小鼠40只,体重(25.0±2.0)克。适应性喂养一周后,将小鼠随机分为对照组(Con)、单纯染砷组(As)、低剂量蛋氨酸组(L-Met)、中剂量蛋氨酸组(M-Met)和高剂量蛋氨酸组(H-Met),每组8只。染毒期间各实验组小鼠以自由饮水方式饮用50mg/L亚砷酸钠溶液,对照组小鼠饮蒸馏水,染毒时间为4周。从染砷的第4周起同时腹腔内注射100mg/kg体重、200mg/kg体重或400mg/kg体重蛋氨酸溶液(用生理盐水配制),对照组和单纯染砷组腹腔注射生理盐水,共注射7天。末次注射后24h内处死小鼠,摘眼球取血,并快速取肝和脑组织,-40℃冰箱冷冻保存。
2、检测指标与方法
(1)血及肝/脑组织中不同砷形态测定:氢化物发生-超低温捕获-原子吸收分光光度法。
(2)谷氨酰胺合成酶活性测定:γ-谷氨酰转移酶的非生理学催化反应。
(3)谷氨酸含量测定:采用南京建成试剂盒测定。
(4)一氧化氮合酶活性测定:采用南京建成试剂盒测定。
(5)一氧化氮含量测定:采用南京建成试剂盒测定。
(6)组织蛋白含量测定:双缩脲法。
(7)血和肝组织中GSH含量测定:二硫双硝基苯甲酸(DTNB)法。
3、统计分析
检测数据输入计算机,用SPSS13.0进行数据分析与处理。血和脑中各砷形态含量不呈正态分布,采用秩和检验(Kruskal-Wallis test),组间比较采用秩次代替原变量进行ANOVA及SNK参数分析。其它指标的统计分析采用ANOVA及SNK的参数分析。
结果
各染砷组小鼠肝、血和脑中iAs、MMA、DMA和TAs含量均显著高于对照组。与As组比较,给予Met的各组小鼠肝中iAs含量均显著下降,中、高剂量Met组的DMA含量显著升高;给予Met的各组小鼠血和脑中iAs、MMA、DMA和TAs含量均显著降低;各剂量Met组小鼠的肝和血中PMI和SMI均有升高,其中各剂量Met组小鼠肝中PMI与As组比较差异显著。与对照组比较,As组小鼠脑中GS、NOS活性和NO含量及血和肝中GSH含量均显著降低,脑中Glu含量显著升高。与As组比较,中、高剂量Met组小鼠脑中GS活性和NO含量显著升高;高剂量Met组小鼠脑中的Glu含量显著降低,NOS活性显著升高;高剂量Met组小鼠血中GSH含量显著升高;中、高剂量Met组小鼠肝中GSH含量显著升高。且均与对照组比较无显著差异。
结论
1、外源性蛋氨酸可以促进肝中iAs的甲基化代谢,加速iAs转变成MMA和DMA。
2、外源性蛋氨酸通过促进iAs在肝中甲基化代谢过程,加速了体内砷的排泄,从而减少血中各砷形态的含量。
3、外源性蛋氨酸通过降低血中各砷形态的含量,减少了进入脑组织内各砷形态的含量,进而改善砷对脑组织Glu和NO代谢的影响。
4、外源性蛋氨酸通过其抗氧化作用,减轻了砷与GSH的结合,改善脑组织内的氧化应激状态。
Introduction
Arsenic-contaminated groundwater is a global environmental health concern, and the predominant form of arsenic in groundwater is inorganic arsenic (iAs). iAs taken up through the first pass is metabolized in liver to dimethylarsinic acid (DMA) by consecutive reduction and oxidative methylations. S-adenosyl-L-methionine (SAM) is the requisite in arsenic methylation. SAM is a conjugate of methionine and the adenosine moiety of ATP, and catalyzed by methionine adenosyltransferase.
Glutamate (Glu) is a main neurotransmitters in excitatory synapse transmission of central nervous system (CNS) and glutamine synthetase (GS) plays a key role in converting glutamate into glutamine in brain. Nitric oxide (NO) is an important messenger molecules and neurotransmitters in the CNS, and is produced by nitric oxide synthase (NOS) catalyzed the L-arginine. In our previous studying, we found arsenic exposure lead to abnormality of Glu and NO metabolism, which had adverse effects on CNS.
The main purpose of this study was to explore whether or not administration of exogenous methionine could modulate arsenic methylation in vivo, and in turn could improve the adverse effects of arsenic on different tissues.
Materials and Methods
1. Animals and treatment
Select forty female and healthy mice, whose weights are between 25.0±2.0g. After one-week adaptation, mice were divided randomly into two groups, Mice in the experimental group were exposed to sodium arsenite through drinking water contaminated with 50 mg/L arsenic for four consecutive weeks, and then subdivided into four groups with eight mice in each group. Mice in different groups were treated intraperitoneally with saline solution (As group), 100mg/kg body weight (b.w) methionine (L-Met group), 200mg/kg body weight (b.w) methionine (M-Met group), 400mg/kg body weight (b.w) methionine (H-Met group) respectively for seven days, while exposure to arsenic contaminated water was continued. Twenty-four hours after cessation of administration, mice were anaesthetized and rapidly dissected. Samples of blood, liver and brain were removed immediately and kept in a -40℃freezer until arsenic species analysis.
2. Methods
(1) The concentrations of different species of As in liver, blood and brain-hydride generation-cold iron capture-atomic absorption spectrophotometry.
(2) The activities of glutamine synthetase-the formation ofγ-glutamyl hydroxamate by the absorbance of the solution at 535nm.
(3) The concentrations of glutamate-kits produced by Nanjing jiancheng.
(4) The activities of nitric oxide synthase- kits produced by Nanjing jiancheng.
(5) The concentrations of nitric oxide- kits produced by Nanjing jiancheng.
(6) The concentrations of proteins- biuret method.
(7) The concentrations of GSH in blood and liver- DTNB method.
3. Statistics
The data were input into computers, analyzed and treated by the SPSS 13.0. The concentrations of different species of As in blood and brain did not show the normal distribution, so using the Kruskal-Wallis test. Other index were analyzed by analysis of variance (ANOVA).
Results
The levels of iAs, MMA, DMA and TAs in the liver, blood and brain of mice in experimental groups were significantly higher than in control. Comparing with As group, the levels of iAs in the liver as well as the levels of iAs, MMA, DMA and TAs in the brain and blood were significantly decreased and the primary methylation index in the liver were significantly increased of mice in groups of methionine administration. The levels of DMA in the liver of mice in both M-Met and H-Met groups were also much higher than that in As group. On the other hand, comparing with control group, activities of GS and NOS as well as contents of NO in brain and contents of GSH in the blood and liver were significantly decreased, whereas contents of Glu in the brain were significantly increased of mice in As group. Comparing with As group, activities of GS and contents of NO in the brain of mice in both M-Met and H-Met groups were significantly increased, and contents of Glu were significantly decreased and activities of NOS were significantly increased in the brain of mice in H-Met group. Contents of GSH in the blood of mice in H-Met group were much higher than that in As group, and contents of GSH in the liver of mice in both M-Met and H-Met groups were also much higher than that in As group.
Conclusions
1. Administration of exogenous methionine could modulate arsenic methylation in liver, and promote the production of MMA and DMA through iAs metabolism.
2. Administration of exogenous methionine could change the arsenic species in blood by affecting the methylation of arsenic and promoting the excretion of arsenic species in liver.
3. Administration of exogenous methionine could reduce the arsenic species in brain by decreasing the arsenic species in blood, and then improve the arsenic-induced effects on metabolism of Glu and NO in brain.
4. Administration of exogenous methionine could improve the oxidative stress in brain through antioxidation.
地方性饮水型砷中毒是我国主要的地方病之一。水砷是人群砷暴露的主要摄入途径,饮水中的砷形态主要是无机砷(inorganic arsenic,iAs)。iAs进入体内后,经过二次氧化甲基化和二次的还原过程,最终被催化生成五价二甲基砷(Dimethylarsinic acid,DMA~(5+))。S-腺苷甲硫氨酸(S-adenosyl-L-methionine,SAM)作为甲基供体,在砷的甲基化代谢中起重要作用,而蛋氨酸(Methionine,Met)在S-腺苷甲硫氨酸合酶的作用下可以被ATP激活生成SAM。
谷氨酸(Glutamate,Glu)是中枢神经系统中兴奋性突触传递的主要神经递质,谷氨酰胺合成酶(Glutamine synthetase,GS)是Glu代谢的关键酶。一氧化氮(Nitricoxide,NO)是中枢神经系统中的重要信使分子和神经递质,由一氧化氮合酶(Nitricoxide synthase,NOS)催化L-精氨酸产生。我们前期的研究结果显示,亚慢性砷暴露可引起小鼠脑组织Glu和NO代谢的异常。
本研究拟通过给予饮水砷暴露小鼠不同剂量的外源性Met,探讨Met对小鼠各组织器官中砷形态的影响,进而探讨Met对改善砷在不同组织中毒性作用的影响,为指导饮水型地方性砷中毒的防治工作提供实验依据。
对象和方法
1、实验动物与染毒
雌性健康昆明种小鼠40只,体重(25.0±2.0)克。适应性喂养一周后,将小鼠随机分为对照组(Con)、单纯染砷组(As)、低剂量蛋氨酸组(L-Met)、中剂量蛋氨酸组(M-Met)和高剂量蛋氨酸组(H-Met),每组8只。染毒期间各实验组小鼠以自由饮水方式饮用50mg/L亚砷酸钠溶液,对照组小鼠饮蒸馏水,染毒时间为4周。从染砷的第4周起同时腹腔内注射100mg/kg体重、200mg/kg体重或400mg/kg体重蛋氨酸溶液(用生理盐水配制),对照组和单纯染砷组腹腔注射生理盐水,共注射7天。末次注射后24h内处死小鼠,摘眼球取血,并快速取肝和脑组织,-40℃冰箱冷冻保存。
2、检测指标与方法
(1)血及肝/脑组织中不同砷形态测定:氢化物发生-超低温捕获-原子吸收分光光度法。
(2)谷氨酰胺合成酶活性测定:γ-谷氨酰转移酶的非生理学催化反应。
(3)谷氨酸含量测定:采用南京建成试剂盒测定。
(4)一氧化氮合酶活性测定:采用南京建成试剂盒测定。
(5)一氧化氮含量测定:采用南京建成试剂盒测定。
(6)组织蛋白含量测定:双缩脲法。
(7)血和肝组织中GSH含量测定:二硫双硝基苯甲酸(DTNB)法。
3、统计分析
检测数据输入计算机,用SPSS13.0进行数据分析与处理。血和脑中各砷形态含量不呈正态分布,采用秩和检验(Kruskal-Wallis test),组间比较采用秩次代替原变量进行ANOVA及SNK参数分析。其它指标的统计分析采用ANOVA及SNK的参数分析。
结果
各染砷组小鼠肝、血和脑中iAs、MMA、DMA和TAs含量均显著高于对照组。与As组比较,给予Met的各组小鼠肝中iAs含量均显著下降,中、高剂量Met组的DMA含量显著升高;给予Met的各组小鼠血和脑中iAs、MMA、DMA和TAs含量均显著降低;各剂量Met组小鼠的肝和血中PMI和SMI均有升高,其中各剂量Met组小鼠肝中PMI与As组比较差异显著。与对照组比较,As组小鼠脑中GS、NOS活性和NO含量及血和肝中GSH含量均显著降低,脑中Glu含量显著升高。与As组比较,中、高剂量Met组小鼠脑中GS活性和NO含量显著升高;高剂量Met组小鼠脑中的Glu含量显著降低,NOS活性显著升高;高剂量Met组小鼠血中GSH含量显著升高;中、高剂量Met组小鼠肝中GSH含量显著升高。且均与对照组比较无显著差异。
结论
1、外源性蛋氨酸可以促进肝中iAs的甲基化代谢,加速iAs转变成MMA和DMA。
2、外源性蛋氨酸通过促进iAs在肝中甲基化代谢过程,加速了体内砷的排泄,从而减少血中各砷形态的含量。
3、外源性蛋氨酸通过降低血中各砷形态的含量,减少了进入脑组织内各砷形态的含量,进而改善砷对脑组织Glu和NO代谢的影响。
4、外源性蛋氨酸通过其抗氧化作用,减轻了砷与GSH的结合,改善脑组织内的氧化应激状态。
Introduction
Arsenic-contaminated groundwater is a global environmental health concern, and the predominant form of arsenic in groundwater is inorganic arsenic (iAs). iAs taken up through the first pass is metabolized in liver to dimethylarsinic acid (DMA) by consecutive reduction and oxidative methylations. S-adenosyl-L-methionine (SAM) is the requisite in arsenic methylation. SAM is a conjugate of methionine and the adenosine moiety of ATP, and catalyzed by methionine adenosyltransferase.
Glutamate (Glu) is a main neurotransmitters in excitatory synapse transmission of central nervous system (CNS) and glutamine synthetase (GS) plays a key role in converting glutamate into glutamine in brain. Nitric oxide (NO) is an important messenger molecules and neurotransmitters in the CNS, and is produced by nitric oxide synthase (NOS) catalyzed the L-arginine. In our previous studying, we found arsenic exposure lead to abnormality of Glu and NO metabolism, which had adverse effects on CNS.
The main purpose of this study was to explore whether or not administration of exogenous methionine could modulate arsenic methylation in vivo, and in turn could improve the adverse effects of arsenic on different tissues.
Materials and Methods
1. Animals and treatment
Select forty female and healthy mice, whose weights are between 25.0±2.0g. After one-week adaptation, mice were divided randomly into two groups, Mice in the experimental group were exposed to sodium arsenite through drinking water contaminated with 50 mg/L arsenic for four consecutive weeks, and then subdivided into four groups with eight mice in each group. Mice in different groups were treated intraperitoneally with saline solution (As group), 100mg/kg body weight (b.w) methionine (L-Met group), 200mg/kg body weight (b.w) methionine (M-Met group), 400mg/kg body weight (b.w) methionine (H-Met group) respectively for seven days, while exposure to arsenic contaminated water was continued. Twenty-four hours after cessation of administration, mice were anaesthetized and rapidly dissected. Samples of blood, liver and brain were removed immediately and kept in a -40℃freezer until arsenic species analysis.
2. Methods
(1) The concentrations of different species of As in liver, blood and brain-hydride generation-cold iron capture-atomic absorption spectrophotometry.
(2) The activities of glutamine synthetase-the formation ofγ-glutamyl hydroxamate by the absorbance of the solution at 535nm.
(3) The concentrations of glutamate-kits produced by Nanjing jiancheng.
(4) The activities of nitric oxide synthase- kits produced by Nanjing jiancheng.
(5) The concentrations of nitric oxide- kits produced by Nanjing jiancheng.
(6) The concentrations of proteins- biuret method.
(7) The concentrations of GSH in blood and liver- DTNB method.
3. Statistics
The data were input into computers, analyzed and treated by the SPSS 13.0. The concentrations of different species of As in blood and brain did not show the normal distribution, so using the Kruskal-Wallis test. Other index were analyzed by analysis of variance (ANOVA).
Results
The levels of iAs, MMA, DMA and TAs in the liver, blood and brain of mice in experimental groups were significantly higher than in control. Comparing with As group, the levels of iAs in the liver as well as the levels of iAs, MMA, DMA and TAs in the brain and blood were significantly decreased and the primary methylation index in the liver were significantly increased of mice in groups of methionine administration. The levels of DMA in the liver of mice in both M-Met and H-Met groups were also much higher than that in As group. On the other hand, comparing with control group, activities of GS and NOS as well as contents of NO in brain and contents of GSH in the blood and liver were significantly decreased, whereas contents of Glu in the brain were significantly increased of mice in As group. Comparing with As group, activities of GS and contents of NO in the brain of mice in both M-Met and H-Met groups were significantly increased, and contents of Glu were significantly decreased and activities of NOS were significantly increased in the brain of mice in H-Met group. Contents of GSH in the blood of mice in H-Met group were much higher than that in As group, and contents of GSH in the liver of mice in both M-Met and H-Met groups were also much higher than that in As group.
Conclusions
1. Administration of exogenous methionine could modulate arsenic methylation in liver, and promote the production of MMA and DMA through iAs metabolism.
2. Administration of exogenous methionine could change the arsenic species in blood by affecting the methylation of arsenic and promoting the excretion of arsenic species in liver.
3. Administration of exogenous methionine could reduce the arsenic species in brain by decreasing the arsenic species in blood, and then improve the arsenic-induced effects on metabolism of Glu and NO in brain.
4. Administration of exogenous methionine could improve the oxidative stress in brain through antioxidation.
引文
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27 Pi JB,Yamauchi H,Kumagai Y,et al.Evidence for induction of oxidative stress caused by chronic exposure of Chinese residents to arsenic contained in drinking water.Environ Health Perspect.2002;100(4):331-336.
28 Kalia K,Narula GD,Kannan GM,et al.Effects of combined administration of captopril and DMSA on arsenite induced oxidative stress and blood and tissue arsenic concentration in rats.Comp Biochem Physiol C Toxicol Pharmacol.2007;144(4):372-379.
29 Nandi D,Patra RC,Swarup D.Effect of cysteine,methionine,ascorbic acid and thiamine on arsenic-induced oxidative stress and biochemical alterations in rats.Toxicology.2005;211:26-35.
1 Xu Y, Wang Y, Zheng Q, et al. Association of oxidative stress with arsenic methylation in chronic arsenic-exposed children and adults. Toxicol Appl Pharmacol. 2008; 232(1): 142-149.
2 Chen Y, Hall M, Graziano JH, et al. A prospective study of blood selenium levels and the risk of arsenic-related premalignant skin lesions. Cancer Epidemiol Biomarkers Prev. 2007; 16: 207-213.
3 Vahter ME. Interactions between arsenic-induced toxicity and nutrition in early life. J Nutr. 2007; 137:2798-804.
4 Singh N, Kumar D, Raisuddin S, et al. Genotoxic effects of arsenic: prevention by functional food-jaggery. Cancer Lett. 2008; 268(2): 325-330.
5 Manna P, Sinha M, Sil PC. Arsenic-induced oxidative myocardial injury: protective role of arjunolic acid. Arch Toxicol. 2008; 82(3): 137-49.
6 Yoshida T, Yamauchi H, Sun GF. Chronic health effects in people exposed to arsenic via the drinking water: dose-response relationships in review. Toxicol Appl Pharmacol. 2004; 198: 243-52.
7 Hayakawa T, Kobayashi Y, Cui X, et al. A new metabolic pathway of arsenite: arsenic-glutathione complexes are substrates for human arsenic methyltransferase Cyt19. Arch Toxicol. 2005; 79: 183-191.
8 Aposhian HV, Zakharyan RA, Avram MD, et al. A review of the enzymology of As metabolism and a new potential role of hydrogen peroxide in detoxication of the trivalent As species. Toxicol Appl Pharmacol. 2004; 198: 327-335.
9 Jin YP, Sun G, Li X, et al. Study on the toxic effects induced by different arsenicals in primary cultured rat astroglia. Toxicol Appl Pharmacol. 2004; 196: 396-403.
10 Heck JE, Gamble MV, Chen Y, et al. Consumption of folate-related nutrients and metabolism of arsenic in Bangladesh. Am J Clin Nutr. 2007; 85: 1367-74.
11 Gamble MV, Liu X, Ahsan H, et al. Folate, homocysteine, and arsenic metabolism in arsenic-exposed individuals in Bangladesh. Environ Health Perspect. 2005; 113: 1683-88.
12 Chung JS, Kalman DA, Moore LE, et al. Family correlations of As methylation patterns in children and parents exposed to high concentration of As in drinking water. Environ Health Perspect. 2002; 110: 729-733.
13 Radabaugh TR, Sampayo-Reyes A, Zakharyan RA, et al. Arsenate reductase II. Purine nucleoside phosphorylase in the presence of dihydrolipoic acid is a route for reduction of arsenate to arsenite in mammalian systems. Chem Res Toxicol. 2002; 15: 692-698.
14 Zakharyan RA, Sampayo-Reyes A, Healy SM, et al. Human monomethylarsonic acid [MMA(V)] reductase is a member of the glutathione-S-transferase superfamily. Chem Res Toxicol. 2001; 14: 1051-7.
15 Lin S, Shi Q, Nix FB, et al. A novel S-adenosyl-L-methionine: Arsenic (Ⅲ) methyltransferase from rat liver cytosol.J Biol Chem.2002;277:10795-803.
16 Waters SB,Devesa V,Fricke MW,et al.Glutathione modulates recombinant rat arsenic(+3oxidation state) methyltransferase-catalyzed formation of trimethylarsine oxide and trimethylarsine.Chem Res Toxicol.2004;17:1621-9.
17 Waters SB,Devesa V,Del Razo L,et al.Endogenous reductants support the catalytic function of recombinant rat Cyt 19,an arsenic methyltransferase.Chem Res Toxicol.2004;17:404-409.
18 Li J,Waters SB,Drobna Z,et al.Arsenic(+3 oxidation state) methyltransferase and the inorganic arsenic methylation phenotype.Toxicol Appl Pharmacol.2005;204:164-9.
19 Radabaugh TR,Aposhian HV.Enzymatic reduction of arsenic compounds in mammalian systems:Reduction of arsenate to arsenite by human liver arsenate reductase.Chem Res Toxicol.2000;13:26-30.
20 Gregus Z,Nemeti B.Biotransformation and toxicokinetics.Purine nucleoside phosphorylase as a cytosolic arsenate reductase.Toxicol Sci.2002;70:13-19.
21 Nemeti B,Gregus Z.Glutathione-dependent reduction of arsenate in human erythrocytessA process independent of purine nucleoside phosphorylase.Toxicol Sci.2004;82:419-428.
22 Zakharyan RA,Sampayo-Reyes A,Healy SM,et al.Human monomethylarsonic acid(MMA(V))reductase is a member of the glutathione-S-transferase superfamily.Chem Res Toxicol.2001;14(8):1501-7.
23 Zakharyan RA,Tsaprailis G,Chowdhury UK,et al.Interactions of sodium selenite,glutathione,arsenic species and omega class human glutathione transferase.Chem Res Toxicol.2005;18:1287-95.
24 Yin ZL,Dahlstrom JE,LeCouteur DG,et al.Immunohistochemistry of omega class glutathione S-transferase in human tissues.J Histochem Cytochem.2001;49:983-988.
25 Sampayo-Reyes A,Zakharyan RA,Healy SM,et al.Monomethylarsonic acid reductase and monomethylarsonous acid in hamster tissue.Chem Res Toxicol.2000;13:1181-6.
26 Spiegelstein O,Lu X,Le XC,et al.Effects of dietary folate intake and folate binding protein-1(Folbpl) on urinary speciation of sodium arsenate in mice.Toxicol Lett.2003;145:167-74.
27 Mishra D,Flora SJ.Differential oxidative stress and DNA damage in rat brain regions and blood following chronic arsenic exposure.Toxicol Ind Health.2008;24(4):247-56.
28 刘井波,彭双清.脂质过氧化作用与线粒体损伤.中国预防医学杂志.2005;6:167-170.
29 周晓倩,伺云,吴君.砷中毒所致氧化应激与肝损伤.中国地方病学杂志.2007;26:114-116.
30 Xu Y,Wang Y,Zheng Q,et al.Association of oxidative stress with arsenic methylation in chronic arsenic-exposed children and adults.Toxicol Appl Pharmacol.2008;232(1):142-9.
31 Xie Y,Liu J,Liu Y,et al.Toxicokinetic and genomic analysis of chronic arsenic exposure in multidrug-resistance mdrla/1b(-/-)double knockout mice.Mol Cell Biochem.2004;255:11-8.
32 Pi J,Yamauchi H,Kumagai Y,et al.Hope of Chinese residents to arsenic contained in drinking water. Environ Health Perspect. 2002; 10: 331-6.
33 Lori M, Stead KP, Pene L, et al. Methylation demand and homocysteine metabolism: effects of dietary provision of creatine and guanidinoacetate. Am J Physiol Endocrinol Metab. 2001; 281: 1095-1100.
34 Craig S, Kenichi C, Dave K, et al. Dietary intake and arsenic methylation in a U.S. population. Environ Health Perspect. 2005; 113: 1153-9.
35 Mary VG, Xinhua L, Habibul A, et al. Folate, homocysteine, and arsenic metabolism in arsenic-exposed individuals in Bangladesh. Environ Health Perspect. 2005; 113: 1683-8.
36 Julia EH, Mary VG, Yu C, et al, Consumption of folate-related nutrients and metabolism of arsenic in Bangladesh. Am J Clin Nutr. 2007; 85: 1367-1374.
37 Nandi D, Patra RC, Swarup D. Effect of cysteine, methionine, ascorbic acid and thiamine on arsenic-induced oxidative stress and biochemical alterations in rats. Toxicology. 2005; 211: 26-35.
38 Flora SJ, Bhadauria S, Kannan GM, et al. Arsenic induced oxidative stress and the role of antioxidant supplementation during chelation: a review. J Environ Biol. 2007; 28(2 Suppl): 333-47.
2 Jin YP,Xi SH,Li X,et al.Arsenic speciation transported through the placenta from mother mice to their newborn pups.Environmental Reaearch.2006;101:349-355.
3 金亚平,李昕,陆春伟,等.饮水砷暴露小鼠肝和脑组织多形态砷检测分析.中国地方病学杂志.2005;24(2):137-139.
4 Hirano S,Cui X,Li S,et al.Difference in uptake and toxicity of trivalent and pentavalent inorganic arsenic in rat heart microvessel endothelial cells.Arch Toxicol.2003;77:305-12.
5 Jin YP,Sun GF,Li X,et al.Study on the toxic effects induced by different arsenicals in primary cultured rat astroglia.Toxicol Appl Pharmacolo.2004;196:396-403.
6 Aposhian HV.Enzymatic methylation of arsenic species and other new approaches to arsenic toxicity.Annu Rev Pharmacol Toxicol.1997;37:397-419.
7 Thomas DJ,Styblo M,Lin S.The cellular metabolism and systemic toxicity of arsenic.Toxicol Appl Pharmacol.2001;176:127-144.
8 Kitchin KT.Recent advances in arsenic carcinogenesis:modes of action,animal model systems,and methylated arsenic metabolites.Toxicol Appl Pharmacol.2001;172:249-261.
9 Craig S,Kenichi C,Dave K,et al.Dietary intake and arsenic methylation in a U.S.population.Environ Health Perspect.2005;113:1153-1159.
10 Hassel B,Bachelard H,Jones P,et al.Trafficking of amino acids between neurons and glia in vivo:Effects of inhibition of glial metabolism by fluoroacetate.J.Cereb.Blood Flow Metab.1997;17:1230-1238.
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12 杨晓运,李智,秦绿叶,等.星形胶质细胞和神经元之间谷氨酸-谷氨酰胺的代谢偶联.生理科学进展.2003;34(4):350-352.
13 Derouiche A,Rauen T.Coincidence of 1-glutamate/1-aspartate transporter(GLAST) and glutamine synthetase(GS) immunoreactions in retinal glia:Evidence for coupling of GLAST and GS in transmitter clearance.Neurosci Res.1995;42:131-143.
14 Hertz L,Dringen R,Schousboe A,et al.Astrocytes:Glutamate producers for neurons.Neurosci Res.1999;57:417-428.
15 Arrigoni E,Rosenberg PA.Nitric oxide-induced adenosine inhibition of hippocampal synaptic transmission depends on adenosine kinase inhibition and is cyclic GMP independent.Eur J Neurosci.2006;24:2471-80.
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17 曲春清,牛玉红,钟媛,等.亚慢性砷暴露对小鼠脑谷氨酸-谷氨酰胺循环通路影响的研究. 环境与健康杂志.2007;24:751-754.
18 Reed DJ,Orrenius S.The role of methionine in glutathione biosynethesis by isolated rat hepatocytes.Biochem Biophys Res Commun.1997;77:1257-64.
19 Renis M,Cardile V,Russo A,et al.Glutamine synthetase activity and HSP70 levels in cultured rat astrocytes:effect of 1-octadecyl-2-methylrae-glycero-3-phosphocholine.Brain Res.1998;783:143-150.
20 钟媛,于霄云,曲春清,等.谷胱甘肽与蛋氨酸对饮水砷暴露小鼠体内砷化物的分布和甲基代谢的影响.卫生研究杂志.2008;37(4):390-392,396.
21 Julia EH,Mary VG,Yu C,et al.Consumption of folate-related nutrients and metabolism of arsenic in Bangladesh.Am J Clin Nutr.2007;85:1367-1374.
22 Hertz L,Yu ACH,Kala C,et al.Neuronal-astrocytic and cytosolic-mitochondrial metabolite trafficking during brain activation,hyperammonemia and energy deprivation.Neurochem Int.2000;37:83-102.
23 Sergio Z,Francisca PS,Juan MD,et al.Decreased nitric oxide production in the rat brain after chronic arsenic exposure.Neurochem Res.2006;31:1069-1077.
24 Pi JB,Kumagai Y,Sun GF,et al.Decreased serum concentrations of nitric oxide metabolites among Chinese in an endemic area of chronic arsenic poisoning in Inner Mongolia.Free Radic Biol Med.2000;28:1137-1142.
25 Pi JB,Horiguchi S,Sun Y,et al.A potential mechanism for the impairment of nitric oxide formation caused by prolonged oral exposure to arsenate in rabbits.Free Rad Biol Med.2003;35:102-113.
26 牛玉红,曲春清,钟媛,等.亚慢性砷暴露小鼠血和肝中砷形态及谷胱甘肽水平检测分析.中国地方病学杂志.2008;27(4):260-263.
27 Pi JB,Yamauchi H,Kumagai Y,et al.Evidence for induction of oxidative stress caused by chronic exposure of Chinese residents to arsenic contained in drinking water.Environ Health Perspect.2002;100(4):331-336.
28 Kalia K,Narula GD,Kannan GM,et al.Effects of combined administration of captopril and DMSA on arsenite induced oxidative stress and blood and tissue arsenic concentration in rats.Comp Biochem Physiol C Toxicol Pharmacol.2007;144(4):372-379.
29 Nandi D,Patra RC,Swarup D.Effect of cysteine,methionine,ascorbic acid and thiamine on arsenic-induced oxidative stress and biochemical alterations in rats.Toxicology.2005;211:26-35.
1 Xu Y, Wang Y, Zheng Q, et al. Association of oxidative stress with arsenic methylation in chronic arsenic-exposed children and adults. Toxicol Appl Pharmacol. 2008; 232(1): 142-149.
2 Chen Y, Hall M, Graziano JH, et al. A prospective study of blood selenium levels and the risk of arsenic-related premalignant skin lesions. Cancer Epidemiol Biomarkers Prev. 2007; 16: 207-213.
3 Vahter ME. Interactions between arsenic-induced toxicity and nutrition in early life. J Nutr. 2007; 137:2798-804.
4 Singh N, Kumar D, Raisuddin S, et al. Genotoxic effects of arsenic: prevention by functional food-jaggery. Cancer Lett. 2008; 268(2): 325-330.
5 Manna P, Sinha M, Sil PC. Arsenic-induced oxidative myocardial injury: protective role of arjunolic acid. Arch Toxicol. 2008; 82(3): 137-49.
6 Yoshida T, Yamauchi H, Sun GF. Chronic health effects in people exposed to arsenic via the drinking water: dose-response relationships in review. Toxicol Appl Pharmacol. 2004; 198: 243-52.
7 Hayakawa T, Kobayashi Y, Cui X, et al. A new metabolic pathway of arsenite: arsenic-glutathione complexes are substrates for human arsenic methyltransferase Cyt19. Arch Toxicol. 2005; 79: 183-191.
8 Aposhian HV, Zakharyan RA, Avram MD, et al. A review of the enzymology of As metabolism and a new potential role of hydrogen peroxide in detoxication of the trivalent As species. Toxicol Appl Pharmacol. 2004; 198: 327-335.
9 Jin YP, Sun G, Li X, et al. Study on the toxic effects induced by different arsenicals in primary cultured rat astroglia. Toxicol Appl Pharmacol. 2004; 196: 396-403.
10 Heck JE, Gamble MV, Chen Y, et al. Consumption of folate-related nutrients and metabolism of arsenic in Bangladesh. Am J Clin Nutr. 2007; 85: 1367-74.
11 Gamble MV, Liu X, Ahsan H, et al. Folate, homocysteine, and arsenic metabolism in arsenic-exposed individuals in Bangladesh. Environ Health Perspect. 2005; 113: 1683-88.
12 Chung JS, Kalman DA, Moore LE, et al. Family correlations of As methylation patterns in children and parents exposed to high concentration of As in drinking water. Environ Health Perspect. 2002; 110: 729-733.
13 Radabaugh TR, Sampayo-Reyes A, Zakharyan RA, et al. Arsenate reductase II. Purine nucleoside phosphorylase in the presence of dihydrolipoic acid is a route for reduction of arsenate to arsenite in mammalian systems. Chem Res Toxicol. 2002; 15: 692-698.
14 Zakharyan RA, Sampayo-Reyes A, Healy SM, et al. Human monomethylarsonic acid [MMA(V)] reductase is a member of the glutathione-S-transferase superfamily. Chem Res Toxicol. 2001; 14: 1051-7.
15 Lin S, Shi Q, Nix FB, et al. A novel S-adenosyl-L-methionine: Arsenic (Ⅲ) methyltransferase from rat liver cytosol.J Biol Chem.2002;277:10795-803.
16 Waters SB,Devesa V,Fricke MW,et al.Glutathione modulates recombinant rat arsenic(+3oxidation state) methyltransferase-catalyzed formation of trimethylarsine oxide and trimethylarsine.Chem Res Toxicol.2004;17:1621-9.
17 Waters SB,Devesa V,Del Razo L,et al.Endogenous reductants support the catalytic function of recombinant rat Cyt 19,an arsenic methyltransferase.Chem Res Toxicol.2004;17:404-409.
18 Li J,Waters SB,Drobna Z,et al.Arsenic(+3 oxidation state) methyltransferase and the inorganic arsenic methylation phenotype.Toxicol Appl Pharmacol.2005;204:164-9.
19 Radabaugh TR,Aposhian HV.Enzymatic reduction of arsenic compounds in mammalian systems:Reduction of arsenate to arsenite by human liver arsenate reductase.Chem Res Toxicol.2000;13:26-30.
20 Gregus Z,Nemeti B.Biotransformation and toxicokinetics.Purine nucleoside phosphorylase as a cytosolic arsenate reductase.Toxicol Sci.2002;70:13-19.
21 Nemeti B,Gregus Z.Glutathione-dependent reduction of arsenate in human erythrocytessA process independent of purine nucleoside phosphorylase.Toxicol Sci.2004;82:419-428.
22 Zakharyan RA,Sampayo-Reyes A,Healy SM,et al.Human monomethylarsonic acid(MMA(V))reductase is a member of the glutathione-S-transferase superfamily.Chem Res Toxicol.2001;14(8):1501-7.
23 Zakharyan RA,Tsaprailis G,Chowdhury UK,et al.Interactions of sodium selenite,glutathione,arsenic species and omega class human glutathione transferase.Chem Res Toxicol.2005;18:1287-95.
24 Yin ZL,Dahlstrom JE,LeCouteur DG,et al.Immunohistochemistry of omega class glutathione S-transferase in human tissues.J Histochem Cytochem.2001;49:983-988.
25 Sampayo-Reyes A,Zakharyan RA,Healy SM,et al.Monomethylarsonic acid reductase and monomethylarsonous acid in hamster tissue.Chem Res Toxicol.2000;13:1181-6.
26 Spiegelstein O,Lu X,Le XC,et al.Effects of dietary folate intake and folate binding protein-1(Folbpl) on urinary speciation of sodium arsenate in mice.Toxicol Lett.2003;145:167-74.
27 Mishra D,Flora SJ.Differential oxidative stress and DNA damage in rat brain regions and blood following chronic arsenic exposure.Toxicol Ind Health.2008;24(4):247-56.
28 刘井波,彭双清.脂质过氧化作用与线粒体损伤.中国预防医学杂志.2005;6:167-170.
29 周晓倩,伺云,吴君.砷中毒所致氧化应激与肝损伤.中国地方病学杂志.2007;26:114-116.
30 Xu Y,Wang Y,Zheng Q,et al.Association of oxidative stress with arsenic methylation in chronic arsenic-exposed children and adults.Toxicol Appl Pharmacol.2008;232(1):142-9.
31 Xie Y,Liu J,Liu Y,et al.Toxicokinetic and genomic analysis of chronic arsenic exposure in multidrug-resistance mdrla/1b(-/-)double knockout mice.Mol Cell Biochem.2004;255:11-8.
32 Pi J,Yamauchi H,Kumagai Y,et al.Hope of Chinese residents to arsenic contained in drinking water. Environ Health Perspect. 2002; 10: 331-6.
33 Lori M, Stead KP, Pene L, et al. Methylation demand and homocysteine metabolism: effects of dietary provision of creatine and guanidinoacetate. Am J Physiol Endocrinol Metab. 2001; 281: 1095-1100.
34 Craig S, Kenichi C, Dave K, et al. Dietary intake and arsenic methylation in a U.S. population. Environ Health Perspect. 2005; 113: 1153-9.
35 Mary VG, Xinhua L, Habibul A, et al. Folate, homocysteine, and arsenic metabolism in arsenic-exposed individuals in Bangladesh. Environ Health Perspect. 2005; 113: 1683-8.
36 Julia EH, Mary VG, Yu C, et al, Consumption of folate-related nutrients and metabolism of arsenic in Bangladesh. Am J Clin Nutr. 2007; 85: 1367-1374.
37 Nandi D, Patra RC, Swarup D. Effect of cysteine, methionine, ascorbic acid and thiamine on arsenic-induced oxidative stress and biochemical alterations in rats. Toxicology. 2005; 211: 26-35.
38 Flora SJ, Bhadauria S, Kannan GM, et al. Arsenic induced oxidative stress and the role of antioxidant supplementation during chelation: a review. J Environ Biol. 2007; 28(2 Suppl): 333-47.