Localization of breast cancer resistance protein (Bcrp) in endocrine organs and inhibition of its transport activity by steroid hormones

Abstract

Breast cancer resistance protein (BCRP) is known for its protective function against the toxic effects of exogenous compounds. In addition to this, a role in the transport of endogenous compounds has been described. Since BCRP in the plasma membrane was shown to be regulated by sex steroids, we investigated the presence and possible role of BCRP in steroid hormone-producing organs. Therefore, the presence and localization of Bcrp was investigated in endocrine organs of wild-type mice. Furthermore, the interaction of various steroid hormones with human BCRP activity was studied. Quantitative PCR revealed Bcrp mRNA in the pituitary and adrenal glands, pancreas, ovary, testis and adipose tissue. Immunohistochemistry revealed the presence of Bcrp in the cortex of the adrenal gland and in plasma membranes of adipocytes. In the pituitary gland, pancreas, ovary and testis, Bcrp was mainly located in the capillaries. The interaction between BCRP and 12 steroid hormones was studied using membrane vesicles of HEK293-BCRP cells. Estradiol, testosterone, progesterone and androstenedione inhibited BCRP-mediated uptake of 3H-estrone sulphate (E1S) most potently, with calculated inhibitory constant (Ki) values of 5.0 ± 0.2, 36 ± 14, 14.7 ± 1.3 and 217 ± 13 μM, respectively. BCRP function was attenuated non-competitively, which implies an allosteric inhibition of BCRP-mediated E1S transport by these steroids. In conclusion, localization of Bcrp in endocrine organs together with the efficient allosteric inhibition of the efflux pump by steroid hormones are suggestive for a role for BCRP in steroid hormone regulation.

Breast cancer resistance protein (Bcrp) and the testis—an unexpected turn of events

“…In the testes, previous studies have shown that Bcrp is expressed mostly in endothelial cells of microvessels in the interstitium and in peritubular myoid cells in the tunica propria of both humans and mice 3,20,21 (Figure 2). Thus, Bcrp is not localized to the BTB in the testes.…”

“…Additionally, the activity, expression and cellular distribution of Bcrp are regulated by steroids. 21,41,42 Collectively, these findings indicate an intimate physiological relationship between Bcrp and the androgen and/or oestrogen microenvironment in the testes, but there are no reports in the literature to assess the role of Bcrp in regulating the level of steroids in the seminiferous epithelium, interstitial fluid and/or the rete testis compartment. However, Bcrp 2/2 male mice are fertile, 47 even though these mice display a malfunction in the disposition of phytoestrogens (e.g., genistein, daidzein, coumestrol), 48 suggesting that while it is important to testicular function, its loss in function via deletion in male mice can be superseded by other ABC drug transporters, such as P-glycoprotein and Mrp1.…”

“…In fact, recent studies have shown that steroids, such as oestradiol-17b, testosterone and progesterone, can inhibit the transport activity of Bcrp and upregulate Bcrp expression and its cellular localisation in cancer cells, endothelial cells of the brain and endocrine organs. 21,41,42 Steroids, particularly testosterone and oestrogens, are known to regulate BTB and testicular Bcrp and spermatogenesis XJ Qian et al 456 function, [43][44][45][46] and Bcrp plays a significant role in regulating the transport of steroids across the myoid cells and Sertoli cells at the apical ES (Table 1). Additionally, the activity, expression and cellular distribution of Bcrp are regulated by steroids.…”

“…20,21,48 Unlike P-glycoprotein, which is localized to the BTB and expressed by Sertoli cells, Leydig cells and late spermatids, 20,50,51 and Mrp1, which is also localized to Sertoli cells at the BTB in humans and mice, 20,52 , but not in endothelial cells in the microvessels of rat testes, 53 Bcrp is not found at the BTB in rat testes. 20,21,33 Recent studies have shown that Bcrp is also expressed by Sertoli cells and late spermatids (steps 17-18, but not step 19) in rat testes in a tightly stage-specific pattern at the Sertoli/spermatid interface at the apical ES, in stage VI-VIII tubules (Figure 3). 33 Bcrp is a component of the apical ES A recent study showed that Bcrp structurally interacts with actin and actin-related protein 3 (Arp3), which together with Arp2 form the Arp2/3 complex.…”

Effect of ursodeoxycholic acid treatment on the altered progesterone and bile acid homeostasis in the mother‐placenta‐foetus trio during cholestasis of pregnancy

“…PMS generation could be secondary to enhanced progesterone synthesis because progesterone has been found to stimulate SULT1E1 expression in human endometrial adenocarcinoma cells [39]. Interestingly, progesterone is able to inhibit ABCG2 [40] and hence may affect the ability of the placenta to export ABCG2 substrates toward the maternal circulation.…”