P-GLYCOPROTEIN REGULATES CHEMOSENSITIVITY IN EARLY DEVELOPMENTAL STAGES OF THE MOUSE

被引:27
作者
ELBLING, L
BERGER, W
REHBERGER, A
WALDHOR, T
MICKSCHE, M
机构
[1] Tumor Biology-Cancer Research Inst., University of Vienna
关键词
OOCYTES; EARLY CLEAVAGE EMBRYOS; MDR-GENE PRODUCTS; DRUG RESISTANCE; IN-VITRO IN-VIVO;
D O I
10.1096/fasebj.7.15.7903262
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
The multidrug resistance (MDR) P-glycoprotein (P-gp) is an active transporter associated with chemoresistance of tumor cells. A fundamental aspect not yet entirely clarified is the physiological role of MDR-P-gp in normal mammalian tissues. In this paper we report that multidrug (chemo)resistance is already present in mouse oocytes and early cleavage embryos. Expression of MDR-specific P-gp is detectable by antibody (C219) staining from the primary oocyte onward to the eight-cell embryo. MDR-mRNA is demonstrated in mature oocytes using an Mdr1-specific cDNA probe. Functional activity of P-gp is shown by the efficacy of MDR reversers (verapamil or quinidine) in enhancement of: 1) drug accumulation (daunomycin) in all stages investigated, 2) drug cytotoxicity (daunomycin or mitomycin C-induced developmental impairment) in two-cell embryos cultured for 24 h, and 3) drug cytokinesis-blocking activity (cytochalasin D; our recent findings demonstrate cytochalasins to be substrates for P-gp and to indicate the presence of MDR by their microfilament-disrupting action on cycling cells) in four- and eight-cell embryos cultured for 24 h. Furthermore, functional involvement of P-gp in vivo is demonstrated. Concurrent administration of verapamil increases doxorubicin-induced developmental impairment in the zygote stage during the first cleavage cycle in pregnant females. Results provide evidence that MDR-P-gp has an efficient protective function in early reproduction.
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页码:1499 / 1506
页数:8
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