Abstract
BackgroundMultidrug resistance transporters (MDRs) are transmembrane proteins that efflux metabolites and xenobiotics. They are highly conserved in sequence and function in bacteria and eukaryotes and play important roles in cellular homeostasis, as well as in avoidance of antibiotics and cancer therapies. Recent evidence also documents a critical role in reproductive health and in protecting the ovary from environmental toxicant effects. The most well understood MDRs are MDR-1 (P-glycoprotein (P-gp) also known as ABCB1) and BCRP (breast cancer resistance protein) and are both expressed in the ovary. We have previously shown that MDR-1 mRNA steady state expression changes throughout the murine estrous cycle, but expression appears to increase in association with the surge in estradiol during proestrus.MethodsHere we test the model that MDR-1 and BCRP are regulated by estrogen, the major hormonal product of the ovary. This was performed by administering 6-week-old female mice either sesame oil (vehicle control) or oral ethinyl estradiol at 1 μg, 10 μg, and 100 μg or PROGESTERONE at 0.25mg, 0.5 mg or 1 mg or a combination of both for 5 days. The mice were then sacrificed, and the ovaries were removed and cleaned. Ovaries were used for qPCR, immunoblotting, and immnunolabeling.ResultsWe found that oral ethinyl estradiol did not influence the steady state mRNA of MDR-1 or BCRP. Remarkably, the effect on mRNA levels neither increased or decreased in abundance upon estrogen exposures. Conversely, we observed less MDR-1 protein expression in the groups treated with 1 μg and 10 μg, but not 100 μg of ethinyl estradiol compared to controls. MDR-1 and BCRP are both expressed in pre-ovulatory follicles. When we tested progesterone, we found that MDR-1 mRNA increased at the dosages of 0.25 mg and 0.5 mg, but protein expression levels were not statistically significant. Combined oral ethinyl estradiol and progesterone significantly lowered both MDR-1 mRNA and protein.ConclusionsProgesterone appears to influence MDR-1 transcript levels, or steady state levels. This could have implications for better understanding how MDR-1 can be modulated during times of toxic exposure. Understanding the normal physiology of MDR-1 in the ovary will expand the current knowledge in cancer biology and reproduction.
Highlights
Multidrug resistance transporters (MDRs) are transmembrane proteins that efflux metabolites and xenobiotics
The major adenosine triphosphate (ATP)-binding cassette (ABC) transporters responsible for resistance to anti-cancer chemotherapeutics include MDR-1 (P-glycoprotein) encoded by the human ABCB1 gene located on chromosome 7q21 [4, 5, 7] and Breast Cancer Resistance Protein (BCRP) encoded by the human ABCG2 gene located on chromosome 4q22 [1, 3, 8,9,10]
Immunolocalization of MDR-1 and BCRP Here we show that both A) MDR-1 and B) BCRP appear localized to the oocyte, the granulosa cells of primary, preantral follicles, and antral follicles (Fig. 5)
Summary
Multidrug resistance transporters (MDRs) are transmembrane proteins that efflux metabolites and xenobiotics. They are highly conserved in sequence and function in bacteria and eukaryotes and play important roles in cellular homeostasis, as well as in avoidance of antibiotics and cancer therapies. Multidrug resistance transporters (MDRs) play vital roles in normal physiology of an organism and are notoriously responsible for evasion of antibiotics in bacteria and in pathologic chemotherapeutic evasion in neoplasms. The major ABC transporters responsible for resistance to anti-cancer chemotherapeutics include MDR-1 (P-glycoprotein) encoded by the human ABCB1 gene located on chromosome 7q21 [4, 5, 7] and Breast Cancer Resistance Protein (BCRP) encoded by the human ABCG2 gene located on chromosome 4q22 [1, 3, 8,9,10]
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