Ovarian hormones modulate multidrug resistance transporters in the ovary

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.Electronic supplementary materialThe online version of this article (10.1186/s40834-018-0076-7) contains supplementary material, which is available to authorized users.

The Microbial Communities and Metabolic Profiles of Follicular Fluid in Patients with Premature Ovarian Insufficiency

“…P-gp responded strongly to LH and progesterone, indicating that this transporter plays an important role in regulating oocyte formation and steroidogenesis (28). P-gp and BCRP in ovarian endothelial cells can prevent potentially harmful foreign substances (including drugs and environmental toxins) from entering the body, protecting the ovaries from toxins and metabolite accumulation (29). Therefore, we speculated that ABC transporters are highly important for maintaining the microenvironment of the ovary and protecting the ovary from harmful substance accumulation.…”

Effect of Baicalin-Aluminum Complexes on Fecal Microbiome in Piglets

“…ABC transporters on the cell membrane could be classified as exporters [42] or importers which rely on the direction of transportation against the cytoplasm [43]. The ABC transporters have been shown to be related to the occurrence of multidrug resistance [44], human diseases such as cancer [45], and inflammatory bowel disease [46]. The abundance of ABC transporters enrichment is increased after treatment with BBA, which might be associated with advance of absorption of nutrients, vitamins, and metabolites [47].…”

Genetics of ABCB1 in Cancer

“…Other studies have shown that upon treatment of estrogen, multidrug-resistant ER-α-positive breast cancer cells downregulate P-gp but not ABCB1 RNA [121,122], suggesting a post-transcriptional mechanism of regulation. In an ovarian cancer model, treatment with estrogen also downregulated P-gp protein without amplification of ABCB1; however, they found that treatment with progesterone did increase ABCB1 RNA, and a combination treatment of estrogen and progesterone led to lower ABCB1 RNA and P-gp levels [123]. While conflicting results have arisen regarding estrogen-and ER-α-mediated regulation of ABCB1, it appears that there is a connection worth studying, and outcomes may have important implications in hormone-driven resistant cancers such as breast and ovarian.…”