不同价态砷对大鼠砷代谢相关酶及MRP2影响的研究
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摘要
目的：分析亚砷酸钠(iAS3+)和砷酸氢钠(iAS5+)染毒后,对大鼠二氢尿嘧啶脱氢酶(NAD)、嘌呤核苷磷酸化酶(PNP)、亚甲基四氢叶酸还原酶(MTHFR)、髓过氧化酶(MPO)活力及多药耐药相关蛋白2(MRP2)表达的影响,寻找不同价态砷体内代谢间的差异,为进一步阐明砷毒作用机制提供依据。方法：70只Wistar大鼠随机分成7组,第1组为正常对照组,给予饮用去离子水；第2-4组为染毒无机三价砷(iAS3+)高、中、低剂量组,分别给予20.0、6.7、2.2mg/kg体质量亚砷酸钠溶液；第5-7组为染毒无机五价砷(iAS5+)高、中、低剂量组,分别给予20.0、6.7、2.2mg/kg体质量砷酸氢钠溶液。各组大鼠于染毒90天后处死,采集血样,取肝脏组织,应用酶联免疫分析法(ELISA)测定大鼠血清NAD、肝脏中NAD、PNP、MTHFR、MPO活力的变化,用蛋白印记法(Western-blotting)测定MRP2表达的变化。结果：1.血清和肝脏中iAS3+和iAS5+高剂量组的NAD活力均低于对照组(P<0.05),相同受试物与低剂量组比较,iAS3+的高、中剂量组的NAD活力均低于低剂量组(P<0.05),iAS5+的高剂量组的NAD活力低于低剂量组(P<0.05),中剂量组的NAD活力高于低剂量组(P<0.05),iAS3+和iAS5+同一剂量组比较,iAS3+高剂量组的NAD活力高于iAS5+高剂量组(P<0.05)。2.iAS3+的低剂量组和iAS5+中剂量组PNP的活力高于对组照(P<0.05),不同受试物同剂量组比较,iAS3+高、中剂量组的PNP活力低于iAS5+高、中剂量组,而iAS3+低剂量组的PNP活力高于iAS5+低剂量组(P<0.05)。3.与对照组相比,iAS3+的高、中、低剂量组和iAS5+高中剂量组MTHFR的活力均升高(P<0.05)；相同受试物与低剂量组比较,iAS3+的高剂量组和iAS5+的高、中剂量组MTHFR的活力均升高(P<0.05)；不同受试物同一剂量组比较,iAS3+高、中、低剂量组的MTHFR活力均高于iAS5+的(P<0.05)。4.与对照组相比,iAS3+和iAS5+的高、中、低剂量组MPO的活力均升高(P<0.05)；相同受试物与低剂量组比较,iAS3+和iAS5+的高、中剂量组MPO的活力均降低(P<0.05)；不同受试物同一剂量组比较,iAS3+高、中剂量组的MPO活力均比iAS5+的低(P<0.05)。5.与对照组相比,iAS3+的高、中、低剂量组和iAS5+高中剂量组MRP2蛋白表达均增加(P<0.05)；相同受试物与低剂量组比较,iAS3+和iAS5+的高剂量组MRP2蛋白表达均增加(P<0.05)；不同受试物同剂量组比较,iAS3+高、中、低剂量组的MRP2蛋白表达均强于iAS5+高、中、低剂量组(P<0.05)。结论：一定量的iAS5+可以使大鼠血、肝脏组织中NAD活力上升,剂量过高反面抑制其活性,iAS3+对NAD主要表现为抑制作用。砷可以影响肝脏组织中PNP、MTHFR、MPO的表达,导致其活性增加。随着砷染毒剂量的增加,MRP2农达逐渐上调,从面致使肝细胞膜上MRP2表达代偿性改变。iAS3+组MRP2表达量要大于iAS5+组,可能是由于两者有不同的外排或转运途径,导致在肝脏的代谢径路不同。肝脏中不同价态砷的代谢和毒性与NAD、PNP、MTHFR、MPO的活性和MRP2表达有密切关系。
Objective:To futher explore the mechanism of arsenic toxicology and seek for the differences between sodium arsenite (iAS3+) and sodium hydrogen arsenate (iAS5+) meta-bolism by studing the influence on content of dihydrouracil dehydrogenas (NAD), purine-nucleoside phosphorylase (PNP),5,10-methylenetetrahydrofolate reductase (MTHFR), myeloperoxidase (MPO), multidrug-resistance assoeiated protein 2 (MRP2) in rats which treated with sodium arsenite and sodium hydrogen arsenate. Methods:Seventy wistar rats were divided randomly into seven groups,10 rats each group. Control group was administrated with deionized water. Sodium arsenite high dose group, middle dose group, low dose group were administrated with different concentrations of sodium arsenite:20.0, 6.7,2.2mg/kg BW every the day; Sodium arsenate high dose group, middle dose group, low dose group were administrated with different concentrations of sodium arsenate:20.0, 6.7,2.2mg As/kg BW every the day. Animals were sacrificed 90 days later by cervical dislocation to collect the blood and Liver, the content of NAD, PNP, MTHFR, MPO were detected by ELISA and expression of MRP2 in the membrane of hepatocyte was determined by Western blotting. Results:1.Comparing the content between control group and iAS5+ high dose group, the difference was statistically significant (P<0.05). The NAD content in the high dose group and middle dose group were significantly lower than the low dose group (P<0.05). But for iAS5+, the NAD content in the high dose was significantly lower than the low dose group (P<0.05). Comparing the matched doses group of iAS5+ and iAS3+, the NAD content of iAS3+ in the high dose group was significantly higher than iAS5+(P<0.05), but the NAD content of iAS3+ in the middle dose group was significantly lower than iAS5+(P<0.05).2.The PNP content of iAS3+ low dose group and iAS5+ middle dose group were higher than control group (P<0.05). Comparing the matched doses group of iAS5+ and iAS3+, the PNP content of iAS3+ high、middle dose group were lower than iAS'+, and the PNP content of iAS3+ low dose group were significantly lower than iAS5+ low dose group(P<0.05).3. Compared with the control group, MTHFR levels of iAS3+ high, middle and low dose group and iAS51 high dose group iAS5+ were increased(P<0.05); Comparing the matched doses group of iAS5+ and iAS3+, MTHFR content of iAS3+ high, middle and low dose group was higher than iAS5 (P<0.05).4. Comparing the content with control group, MPO levels of iAS3+ and iAS5 high, middle and low dose group were increased (P<0.05); Comparing the content between the same test substance and the low dose group, MPO levels of iAS3+ and iAS5+ the high dose group were lower (P<0.05); Comparing the matched doses group of iAS5+ and iAS3+, MPO content of iAS3+ high dose group was lower than iAS5+ (P<0.05).5. Compared to control group, MRP2 protein levels of iAS3+ high, middle, low dose group and iAS5+ high dose group were increased (P<0.05); Comparing the protein levels betweer the same test substance and the low dose group, MRP2 protein levels of iAS3+and iAS5+ high dose group were increased(P<0.05); Comparing the matched doses group of iAS5+ and iAS3+, MRP2 protein levels of iAS3+ high, middle, low dose group were higher than iAS5+ (P<0.05). Conclusion:A certain content of iAS5+ in blood and liver can increase NAD activity, but high dose inhibites the activity of NAD, iAS3+ inhibites the activity of NAD mostly. Arsenic can increase activities of PNP, MTHFR, MPO in the liver. The expression of MRP2 is increased when arsenic dose is growing up. MRP2 expression of iAS3+ is higher than iAS5+, because they may have different discharge or transport pathway. Arsenic metabolism and toxicity in liver have close relationship with contents of NAD, PNP, MTHFR, MPO and MRP2 expression.
Objective:To futher explore the mechanism of arsenic toxicology and seek for the differences between sodium arsenite (iAS3+) and sodium hydrogen arsenate (iAS5+) meta-bolism by studing the influence on content of dihydrouracil dehydrogenas (NAD), purine-nucleoside phosphorylase (PNP),5,10-methylenetetrahydrofolate reductase (MTHFR), myeloperoxidase (MPO), multidrug-resistance assoeiated protein 2 (MRP2) in rats which treated with sodium arsenite and sodium hydrogen arsenate. Methods:Seventy wistar rats were divided randomly into seven groups,10 rats each group. Control group was administrated with deionized water. Sodium arsenite high dose group, middle dose group, low dose group were administrated with different concentrations of sodium arsenite:20.0, 6.7,2.2mg/kg BW every the day; Sodium arsenate high dose group, middle dose group, low dose group were administrated with different concentrations of sodium arsenate:20.0, 6.7,2.2mg As/kg BW every the day. Animals were sacrificed 90 days later by cervical dislocation to collect the blood and Liver, the content of NAD, PNP, MTHFR, MPO were detected by ELISA and expression of MRP2 in the membrane of hepatocyte was determined by Western blotting. Results:1.Comparing the content between control group and iAS5+ high dose group, the difference was statistically significant (P<0.05). The NAD content in the high dose group and middle dose group were significantly lower than the low dose group (P<0.05). But for iAS5+, the NAD content in the high dose was significantly lower than the low dose group (P<0.05). Comparing the matched doses group of iAS5+ and iAS3+, the NAD content of iAS3+ in the high dose group was significantly higher than iAS5+(P<0.05), but the NAD content of iAS3+ in the middle dose group was significantly lower than iAS5+(P<0.05).2.The PNP content of iAS3+ low dose group and iAS5+ middle dose group were higher than control group (P<0.05). Comparing the matched doses group of iAS5+ and iAS3+, the PNP content of iAS3+ high、middle dose group were lower than iAS'+, and the PNP content of iAS3+ low dose group were significantly lower than iAS5+ low dose group(P<0.05).3. Compared with the control group, MTHFR levels of iAS3+ high, middle and low dose group and iAS51 high dose group iAS5+ were increased(P<0.05); Comparing the matched doses group of iAS5+ and iAS3+, MTHFR content of iAS3+ high, middle and low dose group was higher than iAS5 (P<0.05).4. Comparing the content with control group, MPO levels of iAS3+ and iAS5 high, middle and low dose group were increased (P<0.05); Comparing the content between the same test substance and the low dose group, MPO levels of iAS3+ and iAS5+ the high dose group were lower (P<0.05); Comparing the matched doses group of iAS5+ and iAS3+, MPO content of iAS3+ high dose group was lower than iAS5+ (P<0.05).5. Compared to control group, MRP2 protein levels of iAS3+ high, middle, low dose group and iAS5+ high dose group were increased (P<0.05); Comparing the protein levels betweer the same test substance and the low dose group, MRP2 protein levels of iAS3+and iAS5+ high dose group were increased(P<0.05); Comparing the matched doses group of iAS5+ and iAS3+, MRP2 protein levels of iAS3+ high, middle, low dose group were higher than iAS5+ (P<0.05). Conclusion:A certain content of iAS5+ in blood and liver can increase NAD activity, but high dose inhibites the activity of NAD, iAS3+ inhibites the activity of NAD mostly. Arsenic can increase activities of PNP, MTHFR, MPO in the liver. The expression of MRP2 is increased when arsenic dose is growing up. MRP2 expression of iAS3+ is higher than iAS5+, because they may have different discharge or transport pathway. Arsenic metabolism and toxicity in liver have close relationship with contents of NAD, PNP, MTHFR, MPO and MRP2 expression.
引文
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