Efflux transport of estrogen glucuronides by human MRP2, MRP3, MRP4 and BCRP. Issue 178 (April 2018)

• Record Type: Journal Article
• Authors: Järvinen, Erkka; Deng, Feng; Kidron, Heidi; Finel, Moshe
• Is Part Of: Journal of steroid biochemistry and molecular biology. Issue 178(2017)
• Page Start: 99
• Page End: 107
• Publication Date: 2018-04
• Subjects: E1-S estrone sulfate -- E1-G estrone glucuronide -- E2-3G estradiol-3-glucuronide -- E2-17G estradiol-17β-glucuronide -- E3-3G estriol-3-glucuronide -- E3-16G estriol-16α-glucuronide -- BCRP, ABCG2 breast cancer resistance protein -- MRP, ABCC multidrug resistance associated proteins -- MDR1, P-glycoprotein, P-gp multidrug resistance protein 1 -- UGT UDP-glucuronosyltransferases -- ABC ATP-binding cassette transporters; Drug transporters -- Steroid disposition -- Steroid transport -- Estrogen -- Glucuronides -- Steroid excretion; Steroid hormones -- Periodicals; Biochemistry -- Periodicals; Hormones -- Periodicals; Molecular Biology -- Periodicals; Hormones stéroïdes -- Périodiques; Steroid hormones; Periodicals; 572.579
• DOI: 10.1016/j.jsbmb.2017.11.007
• Languages: English
• ISSNs: 0960-0760

Abstract

Graphical abstract: Highlights: In vitro efflux transport of estrogen glucuronides and estrone-sulfate was studied. E1 -S is a high affinity substrate for BCRP, and it is not transported by MRPs 2–4. BCRP is highly active in the transport of estrone (E1 )- and estradiol (E2 )-3-glucuronide. MRP3 transports estrone, estradiol and estriol (E3 ) glucuronides at rather high affinity. From the tested estrogen glucuronides, MRP4 transported only E3 -16-glucuronide. Abstract: Estrone, estradiol and estriol are endogenous human estrogens that are rapidly conjugated with glucuronic acid in both intestinal and hepatic epithelial cells. The resulting glucuronides, estrone-3-glucuronide (E1 -G), estradiol-3- and 17-glucuronides (E2 -3G and E2 -17G), as well as estriol-3- and 16-glucuronides (E3 -3G and E3 -16G) are found in human plasma and urine. Unlike E2 -17G, the efflux transport of other estrogen glucuronides by human transporters has not yet been investigated comprehensively. We have studied the transport of E1 -G, E2 -3G, E3 -3G, E3 -16G and estrone-3-sulfate (E1 -S), another important estrogen conjugate, using the vesicular transport assay with recombinant human MRP2, MRP3, MRP4, MDR1 and BCRP that were expressed in insect cells. The transport screening assays revealed that whereas E1 -S was a good and specific substrate for BCRP, the less transporter-specific conjugates, E1 -G and E2 -3G, were still transported by BCRP at 10-fold higher rates than E1 -S. BCRP also transported E3 -16G at higher rates than the studied MRPs, while it transported E3 -3G at lower rates than MRP3. MRP2 exhibited lower or equal transport rates of E1 -G, E2 -3G, E3 -3G and E3 -16G in comparison to MRP3 and BCRP in the screening assays, mainly due to its high K m values, between 180 and 790 μM. MRP3 transported all the tested glucuronides at rather similar rates, at K m values below 20 μM, but lower Vmax values than other transporters. In the case of E3 -3G, MRP3 was the most active transporter in the screening assay. MRP4 transported only E3 -16G at considerable rates, while none of the tested estrogen conjugates was transported by MDR1 at higher rates than control vesicles. These new results, in combination with previously reported in vivo human data, stimulate our understanding on the substrate specificity and role of efflux transporters in disposition of estrogen glucuronides in humans.