Role of Breast Cancer Resistance Protein (Bcrp1/Abcg2) in the Extrusion of Glucuronide and Sulfate Conjugates from Enterocytes to Intestinal Lumen

Adachi, Yasuhisa; Suzuki, Hiroshi; Schinkel, Alfred H.; Sugiyama, Yuichi

doi:10.1124/mol.104.007393

Cited by 73 publications

(58 citation statements)

References 19 publications

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“…5). This is also consistent with the observation that excretion of 4-methylumbelliferone glucuronide was also diminished in BCRP knockout mice (26). Moreover, another study showed a 36% and 17% decrease for the apical excretion of benzo [a] pyrene-3-sulfate in Caco-2 cells and TC7 cells, respectively, in the presence of Ko 143 (a specific BCRP inhibitor) (27), although the differences were not as distinct as shown in this paper.…”

Section: Discussionsupporting

confidence: 92%

“…This is one of the rare instances when we observed that a deficiency in single transporter almost completely diminished the cellular excretion of its substrate, in this case a sulfate. Previously, Adachi et al showed that excretion of 4-methylumbelliferone sulfate was also similarly decreased in BCRP knockout mice (26). In addition, BCRP also played a major role in the excretion of genistein glucuronide, as its excretion was decreased 78% in the knockout mice (Fig.…”

Section: Discussionmentioning

confidence: 79%

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Breast Cancer Resistance Protein (BCRP) and Sulfotransferases Contribute Significantly to the Disposition of Genistein in Mouse Intestine

Zhu

Wang

et al. 2010

AAPS J

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Abstract. The low bioavailability of genistein has impeded its development into a therapeutic agent. Our earlier studies indicate that glucuronidation is one of the major barriers to genistein oral bioavailability. This study will determine how sulfotransferases and efflux transporters affect its intestinal disposition. A rodent intestinal perfusion model and S9 fractions were used. Sulfate excretion rates were comparable to glucuronide excretion in mouse small intestine but significantly higher than glucuronide excretion in mouse colon, which is different from rat intestinal disposition but similar to disposition in Caco-2 cells. To define efflux transporter(s) involved in sulfate excretion, two organic anion inhibitors (estrone sulfate and dihydroepiandrosterone sulfate) or a multidrug resistance protein inhibitor (MK-571) were used but neither was able to decrease the excretion of genistein sulfates. In contrast, the excretion of genistein sulfate decreased substantially (>90%) in small intestine of breast cancer resistance protein (BCRP) knockout mice and became undetectable in colon of the knockout mice. The excretion rates of genistein glucuronide in the small intestine of BCRP knockout mice were also significant decreased (78%). This study shows clearly that BCRP facilitates the cellular genistein sulfate excretion by removing sulfates to prevent their backward hydrolysis and to limit substrate inhibition, indicating that BCRP plays a dominant role in genistein sulfate excretion and a significant role in genistein glucuronide excretion in the mouse intestine.

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Section: Discussionsupporting

confidence: 92%

Section: Discussionmentioning

confidence: 79%

Breast Cancer Resistance Protein (BCRP) and Sulfotransferases Contribute Significantly to the Disposition of Genistein in Mouse Intestine

Zhu

Wang

et al. 2010

AAPS J

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“…Breast cancer resistance protein (BCRP/Bcrp/ABCG2), a member of the ATP-binding cassette transporter family, is one of the most important efflux transporters for drug disposition and plays an important role in the transport of phase II conjugates (Adachi et al, 2005). BCRP is expressed not only in multidrug resistance tumor cells but also in normal human tissues, including intestine, liver, kidney, brain endothelium, and placenta.…”

Section: Introductionmentioning

confidence: 99%

Breast Cancer Resistance Protein (ABCG2) Determines Distribution of Genistein Phase II Metabolites: Reevaluation of the Roles of ABCG2 in the Disposition of Genistein

et al. 2012

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ABSTRACT:It was recently proposed that the improved oral bioavailability of genistein aglycone and conjugates in Bcrp1(؊/؊) mice is mainly due to increased intestinal absorption of aglycone and subsequent elevated exposure to conjugation enzymes. Here we tested this proposed mechanism and found that intestinal absorption of genistein aglycone did not increase in Bcrp1(؊/؊) mice compared with wild-type mice using an in situ mouse intestinal perfusion model and that inhibition of breast cancer resistance protein (BCRP) in Caco-2 cells also did not significantly increase permeability or intracellular concentration of aglycone. Separately, we showed that 5-to 10-fold increases in exposures of conjugates and somewhat lower fold increases (<2-fold) in exposures of aglycone were apparent after both oral and intraperitoneal administration in Bcrp1(؊/؊) mice. In contrast, the intestinal and biliary excretion of genistein conjugates significantly decreased in Bcrp1(؊/؊) mice without corresponding changes in aglycone excretion. Likewise, inhibition of BCRP functions in Caco-2 cells altered polarized excretion of genistein conjugates by increasing their basolateral excretion. We further found that genistein glucuronides could be hydrolyzed back to genistein, whereas sulfates were stable in blood. Because genistein glucuronidation rates were 110% (liver) and 50% (colon) higher and genistein sulfation rates were 40% (liver) and 42% (colon) lower in Bcrp1(؊/؊) mice, the changes in genistein exposures are not mainly due to changes in enzyme activities. In conclusion, improved bioavailability of genistein and increased plasma area under the curve of its conjugates in Bcrp1(؊/؊) mice is due to altered distribution of genistein conjugates to the systemic circulation.

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“…In addition, Mrp2 is highly expressed in the duodenum, and its expression decreases from the proximal to the distal region of the small intestine (Maher et al, 2005). Mrp2 also mediates the mucosal efflux of the glucuronide conjugates of xenobiotics into the lumen (Adachi et al, 2005). To identify S-8921G as Mrp2 substrate, transcellular transport of S-8921G was examined in Madin-Darby canine kidney (MDCK) II cells expressing both OATP1B1 and MRP2.…”

mentioning

confidence: 99%

Identification of the Transporters Involved in the Hepatobiliary Transport and Intestinal Efflux of Methyl 1-(3,4-Dimethoxyphenyl)-3-(3-ethylvaleryl)-4-hydroxy-6,7,8-trimethoxy-2-naphthoate (S-8921) Glucuronide, a Pharmacologically Active Metabolite of S-8921

Sakamoto¹,

Kusuhara²,

Horie³

et al. 2008

Drug Metab Dispos

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ABSTRACT:The glucuronide conjugate of methyl 1-(3,4-dimethoxyphenyl)-3-(3-ethylvaleryl)-4-hydroxy-6,7,8-trimethoxy-2-naphthoate (S-8921; S-8921G) is a 6000-fold more potent inhibitor of an ileal apical sodium-dependent bile acid transporter (SLC10A2) than S-8921 and is responsible for the hypocholesterolemic effect of S-8921 in rats. Because S-8921G is formed in the intestine and liver, the present study investigated the transporters involved in the secretion of S-8921G that govern its exposure to the target site and thereby play an important role in its pharmacological action. Or- Furthermore, the secretion clearance of S-8921G to the mucosal side was also significantly lower in everted jejunum sacs from EHBR (9.18 and 20.8 l/min/g tissue). These results suggest that MRP2 is responsible for the secretion of S-8921G to the intestinal lumen and bile and that OATP1B1 and OATP1B3 account for the hepatic uptake. These transporters deliver S-8921G to the target site of its pharmacological action.Hyperlipidemia, especially hypercholesterolemia, is a major risk factor for atherosclerosis, leading to coronary heart disease. In clinical trials, reducing serum low-density lipoprotein (LDL) cholesterol has been shown to reduce the incidence of coronary heart disease and to reverse atherosclerotic lesions in hypercholesterolemic patients (Shepherd et al., 1995). The hypocholesterolemic agents most commonly used are the HMG-CoA reductase inhibitors (so-called statins).Statins have a potent hypocholesterolemic action and few side effects, resulting in good patient compliance. As alternative pharmacological targets for the hypocholesterolemic effect, there is growing interest in inhibition of the intestinal absorption of cholesterol and bile acids.S-8921 is a novel inhibitor of an ileal apical sodium-dependent bile acid transporter (ASBT/SLC10A2) and inhibits the absorption of bile acids from the ileum. The bile acid pool is tightly regulated; thus, inhibition of bile acid reabsorption via ASBT in the ileum by S-8921 would lead to an increase in the biosynthesis of bile acids from cholesterol. This is partly ascribed to the increase in the uptake of plasma LDL cholesterol through the up-regulation of LDL receptors as a result of partial depletion of hepatic cholesterol (Packard and Shepherd, 1982). In addition, S-8921 up-regulates hepatic LDL receptor expression and cholesterol 7␣-hydroxylase in rabbits (Higaki et al., 1998). These events result in a reduction in the plasma cholesterol.Initially, the reduction in plasma cholesterol by S-8921 was ascribed to the direct inhibition of ASBT by S-8921 following p.o. administration. Later, it became evident that the glucuronide conjugate of S-8921 (S-8921G), rather than S-8921 itself, is responsible for Article, publication date, and citation information can be found at

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Role of Breast Cancer Resistance Protein (Bcrp1/Abcg2) in the Extrusion of Glucuronide and Sulfate Conjugates from Enterocytes to Intestinal Lumen

Cited by 73 publications

References 19 publications

Breast Cancer Resistance Protein (BCRP) and Sulfotransferases Contribute Significantly to the Disposition of Genistein in Mouse Intestine

Breast Cancer Resistance Protein (BCRP) and Sulfotransferases Contribute Significantly to the Disposition of Genistein in Mouse Intestine

Breast Cancer Resistance Protein (ABCG2) Determines Distribution of Genistein Phase II Metabolites: Reevaluation of the Roles of ABCG2 in the Disposition of Genistein

Identification of the Transporters Involved in the Hepatobiliary Transport and Intestinal Efflux of Methyl 1-(3,4-Dimethoxyphenyl)-3-(3-ethylvaleryl)-4-hydroxy-6,7,8-trimethoxy-2-naphthoate (S-8921) Glucuronide, a Pharmacologically Active Metabolite of S-8921

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