Disruption of the murine MRP (multidrug resistance protein) gene leads to increased sensitivity to etoposide (VP-16) and increased levels of glutathione.
Disruption of the murine MRP (multidrug resistance protein) gene leads to increased sensitivity to etoposide (VP-16) and increased levels of glutathione.
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发表时间：
1997-12
期刊：
影响因子：
11.2
通讯作者：
A. Lorico;G. Rappa;R. A. Finch;Di Yang;R. A. Flavell;Alan C. Sartorelli
中科院分区：
文献类型：
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作者：
A. Lorico;G. Rappa;R. A. Finch;Di Yang;R. A. Flavell;Alan C. Sartorelli
多药耐药蛋白(MRP)基因与肿瘤细胞的体内外多药耐药相关。为了获得关于其生理作用的信息，胚胎干细胞被用来产生纯合子的小鼠，以破坏MRP基因，导致完全取消MRP的表达。没有观察到生理异常，至少到4个月龄。MRP(+/+)和MRP(-/-)小鼠的存活率、生育力以及一系列组织学、血液学和血清化学参数相似。MRP(-/-)小鼠对依托泊苷磷酸的敏感性增加2倍，并伴有更大的骨髓毒性，而亚砷酸钠的急性毒性在MRP(+/+)和MRP(-/-)小鼠中相当。在MRP(-/-)小鼠的乳房、肺、心脏、肾脏、肌肉、结肠、睾丸、骨髓细胞、血单核白细胞和血红细胞中，谷胱甘肽(GSH)的组织水平升高，而在已知的几乎不表达MRP的器官，如肝脏和小肠中，GSH水平没有变化。GSH的增加并不是由于GSH合成的限速酶--谷氨酰半胱氨酸合成酶的活性增加所致。结果表明，MRP对发育和生长是必不可少的，但在药物解毒和GSH代谢中发挥作用。
The mrp (multidrug resistance protein) gene has been associated with the multidrug resistance of cancer cells in vitro and in vivo. To gain information on its physiological role, embryonic stem cells were used to generate mice homozygous for a disruption of the mrp gene, resulting in complete abrogation of mrp expression. No physiological abnormalities were observed, at least up to 4 months of age. Viability, fertility, and a range of histological, hematological, and serum-chemical parameters were similar in mrp(+/+) and mrp(-/-) mice. mrp(-/-) mice displayed an increased sensitivity to etoposide phosphate (2-fold) accompanied by greater bone marrow toxicity, whereas the acute toxicity of sodium arsenite was equivalent in mrp(+/+) and mrp(-/-) mice. Tissue levels of glutathione (GSH) were elevated in breast, lung, heart, kidney, muscle, colon, testes, bone marrow cells, blood mononuclear leukocytes, and blood erythrocytes of mrp(-/-) mice and were unchanged in organs known to express little if any mrp, such as the liver and small intestine. The increase in GSH was not due to an increase in the activity of gamma-glutamylcysteine synthetase, the rate-limiting enzyme for GSH synthesis. The findings demonstrate that mrp is dispensable for development and growth but exerts a role in drug detoxification and GSH metabolism.