Effects of glutathione depletion on the acute nephrotoxic potential of arsenite and on arsenic metabolism in hamsters.
Effects of glutathione depletion on the acute nephrotoxic potential of arsenite and on arsenic metabolism in hamsters.
复制标题
谷胱甘肽消耗对亚砷酸盐的急性肾毒性潜力和仓鼠砷代谢的影响。
DOI：
10.1016/0041-008x(90)90342-r
复制
发表时间：
1990
影响因子：
3.8
通讯作者：
N. Ishinishi
中科院分区：
文献类型：
--
作者：
M. Hirata;A. Tanaka;A. Hisanaga;N. Ishinishi
我们以前的研究表明，用抑制谷胱甘肽合成的丁硫氨酸亚硫胺(BSO)预处理，可导致摄入亚砷酸钠(5 mg As/kg)的金黄地鼠急性肾功能衰竭和少尿。为了更深入地了解砷代谢与随后的肾毒性发展之间的关系，我们研究了BSO处理前后仓鼠肾脏的排泄、组织滞留、生物转化、药代动力学和组织病理学事件。在给药后72小时内，BSO组动物尿液和粪便中的总砷排泄量是对照组的五倍多(9.2比53.4%)。尽管无机砷的含量随着时间的推移而稳步下降，但在BSO处理的金黄地鼠的血液、肝脏和肾脏中，总砷的含量仍然很高。BSO组大鼠血中无机砷的消除呈现两相消除模式，首先是半衰期为4.5小时的快速组分，其次是半衰期为58.0小时的慢速组分，而对照组的半衰期分别为0.6小时和11.0小时。BSO处理不仅影响无机砷的排泄，而且还影响无机砷的甲基化。BSO/亚砷酸盐联合用药组大鼠出现肾小管坏死，给药后1小时肾小管坏死明显。1小时后，BSO处理组大鼠肾脏无机砷含量是对照组的1.7倍。本研究证明谷胱甘肽耗竭可引起砷中毒的肾毒性表现。
Our previous study showed that pretreatment with buthionine sulfoximine (BSO), which inhibits glutathione synthesis, results in acute renal failure with oliguria in hamsters ingesting sodium arsenite (5 mg As/kg). For a deeper understanding of the relationship between arsenic metabolism and the subsequent development of nephrotoxicity, we studied excretion, tissue retention, biotransformation, pharmacokinetics, and histopathological events in the kidneys of hamsters both with and without BSO pretreatment. The total amount of arsenic excreted in the urine and feces within 72 hr of arsenite administration was more than fivefold lower in BSO-pretreated animals than in the controls without pretreatment (9.2 versus 53.4% of the arsenic dose). The persistence of high amounts of total arsenic was apparent in the blood, liver, and kidneys of BSO-pretreated hamsters, even though the content of inorganic arsenic steadily decreased with time. The disappearance of inorganic arsenic from the blood showed a biphasic elimination pattern characterized first by a rapid component with a half-life of 4.5 hr and second by a slower component with a half-life of 58.0 hr in the BSO-pretreated hamsters, while these half-lives were 0.6 and 11.0 hr, respectively, in the controls. BSO pretreatment not only impaired the excretion of inorganic arsenic, but also impaired its methylation. Combined BSO/arsenite treatment resulted in renal tubular necrosis which was prominent at 1 hr after arsenite administration. By 1 hr, the renal content of inorganic arsenic in the BSO-pretreated animals was 1.7 times higher than that in the controls. This study demonstrates that glutathione depletion elicits the nephrotoxic manifestations of arsenic poisoning.