Multidrug resistant transport activity protects oocytes from chemotherapeutic agents and changes during oocyte maturation

Capsule:
Oocytes have a vast repertoire of multidrug-resistant transporters. These protective effluxers change overall activity during maturation, and inhibition of these transporters increases cell susceptibility to toxicants.

Authors:
Lynae Brayboy, M.D., Nathalie Oulhen, Ph.D., Jeannine Witmyer, Ph.D., Jared Robins, M.D., Sandra Carson, M.D., Gary Wessel

Volume 100, Issue 5, Pages 1428-1435.e7, November 2013

Abstract:

Objective:
To determine the multidrug-resistant transporter (MDR) activity in oocytes and their potential role in oocyte susceptibility to chemotherapy.

Design:
Experimental laboratory study.

Setting:
University and academic center for reproductive medicine.

Subject(s):
Women with eggs retrieved for intracytoplasmic sperm injection cycles and adult female FVBN and B6C3F1 mouse strains.

Intervention(s):
Inhibition of MDR activity in oocytes.

Main Outcome Measure(s):
Efflux activity of MDRs with the use of quantitative fluorescent dye efflux, and oocyte cell death when exposed to chemotherapy.

Result(s):
Oocytes effluxed fluorescent reporters, and this activity was significantly reduced in the presence of the MDR inhibitor PSC 833. Geminal vesicle oocytes were more efficient at efflux than metaphase 2 oocytes. Human oocytes exposed to cyclophosphamide and PSC 833 showed cell death with the use of two different viability assays compared with control samples and those exposed to cyclophosphamide alone. Immunoblots detected MDR-1 in all oocytes, with the greatest accumulation in the geminal vesicle stage.

Conclusion(s):
Oocytes have a vast repertoire of active MDRs. The implications of this study are that these protective mechanisms are important during oogenesis and that these activities change with maturation, increasing susceptibility to toxicants. Future directions may exploit the up-regulation of these transporters during gonadotoxic therapy.

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