Normal viability and altered pharmacokinetics in mice lacking mdr1-type (drug-transporting) P-glycoproteins
Normal viability and altered pharmacokinetics in mice lacking mdr1-type (drug-transporting) P-glycoproteins
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DOI：
10.1073/pnas.94.8.4028
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发表时间：
1997-04-15
影响因子：
11.1
通讯作者：
Borst, P
中科院分区：
文献类型：
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作者：
Schinkel, AH;Mayer, U;Borst, P
mdr 1型P-糖蛋白（P-gps）通过从细胞主动挤出多种药物而赋予癌细胞多药耐药性。为了研究它们的生理作用，我们产生了mdr 1b基因遗传缺陷的小鼠[mdr 1b（-/-）小鼠]和mdr 1a和mdr 1b基因遗传缺陷的小鼠[mdr 1a/1b（-/-）小鼠]。尽管推测归因于mdr 1型P-GPS的功能的主机，我们没有发现任何生理异常的菌株。mdr 1a/1b（-/-）小鼠的活力、生育力和一系列组织学、血液学、血清化学和免疫学参数均未出现异常。妊娠子宫中正常存在的高水平mdr 1b P-gp并不能保护胎儿免受母体血液中药物（地高辛）的影响，尽管该蛋白确实减少了肾上腺和卵巢中的药物蓄积。在药理学上，mdr 1a/1b（-/-）小鼠的表现与先前分析的mdr 1a（-/-）小鼠相似，例如，显示出脑渗透增加和地高辛消除减少。然而，mdr 1a和mdr 1b P-GPS都有助于从造血祖细胞中挤出罗丹明，这表明内源性mdr 1型P-GPS在保护骨髓免受细胞毒性抗癌药物的侵害中具有潜在作用。这一点，以及mdr 1a/1b（-/-）小鼠的正常生存能力，对在癌症和其他化疗中使用P-gp阻断剂具有意义。mdr 1a/1b（-/-）小鼠为进一步研究P-gp转运蛋白的药理作用和分析P-gp阻断药物的特异性和有效性提供了一个有用的模型系统。
The mdr1-type P-glycoproteins (P-gps) confer multidrug resistance to cancer cells by active extrusion of a wide range of drugs from the cell. To study their physiological roles, we have generated mice genetically deficient in the mdr1b gene [mdr1b (-/-) mice] and in both the mdr1a and mdr1b genes [mdr1a/1b (-/-) mice]. In spite of the host of functions speculatively attributed to the mdr1-type P-gps, we found no physiological abnormalities in either strain. Viability, fertility, and a range of histological, hematological, serum-chemical, and immunological parameters were not abnormal in mdr1a/1b (-/-) mice. The high level of mdr1b P-gp normally present in the pregnant uterus did not protect fetuses from a drug (digoxin) in the bloodstream of the mother, although the protein did reduce drug accumulation in the adrenal gland and ovaries. Pharmacologically, mdr1a/1b (-/-) mice behaved similarly to the previously analyzed mdr1a (-/-) mice, displaying, for instance, increased brain penetration and reduced elimination of digoxin. However, both mdr1a and mdr1b P-gps contributed to the extrusion of rhodamine from hematopoietic progenitor cells, suggesting a potential role for the endogenous mdr1-type P-gps in protection of bone marrow against cytotoxic anticancer drugs. This, and the normal viability of mdr1a/1b (-/-) mice, has implications for the use of P-gp-blocking agents in cancer and other chemotherapy. mdr1a/1b (-/-) mice should provide a useful model system to further test the pharmacological roles of the drug-transporting P-gps and to analyze the specificity and effectivity of P-gp-blocking drugs.