Inhibitory Effects of Herbal Extracts on Breast Cancer Resistance Protein (BCRP) and Structure-Inhibitory Potency Relationship of Isoflavonoids

Abstract

The inhibition of intestinal breast cancer resistance protein (BCRP), which restricts the absorption of xenobiotics, may increase the systemic availability of its substrates. The aim of this study was to evaluate the inhibitory effects of herbal extracts and their constituents on BCRP-mediated transport. The inhibitory effects of 9 herbal extracts and 23 isoflavonoids, including soybean-derived isoflavones, on BCRP-mediated methotrexate (MTX) transport were evaluated using BCRP-expressing membrane vesicles. The structure-inhibitory potency relationship was investigated by multiple factor analysis. Extracts of soybean, Gymnema sylvestre, black cohosh and passion flower and rutin strongly inhibited BCRP-mediated transport of MTX at 1 mg/ml, while inhibition by chlorella, milk thistle and Siberian ginseng extracts was weak. Among the 23 isoflavonoids examined, all of which inhibited BCRP-mediated transport, coumestrol showed the most potent inhibition (IC(50)=63 nM). The inhibitory potencies of 6 isoflavonoid glucosides were 10- to 100-fold lower than those of the corresponding aglycones. The addition of a 5-hydroxyl or 6-methoxyl moiety tended to potentiate the inhibition. The inhibitory potency of daidzein was decreased 100-fold by 7-glucuronidation, but was virtually unaffected by 4'-sulfation. Thus, some herbal and dietary supplements and isoflavonoids may increase the systemic availability of BCRP substrates when concomitantly given orally.

Breast Cancer Resistance Protein (ABCG2) in Clinical Pharmacokinetics and Drug Interactions: Practical Recommendations for Clinical Victim and Perpetrator Drug-Drug Interaction Study Design

“…Natural Products. Several diet-derived/natural product constituents, such as curcumin, daidzein, genistein, chrysin, 7,8-benzoflavone, and glycyrrhetic acid, have been shown to inhibit human BCRP in vitro (Zhang et al, 2005a;Yoshida et al, 2008;Merino et al, 2010;Tamaki et al, 2010). In addition, a mixture of the soy isoflavones genistein and daidzein was shown to inhibit Bcrp in wild-type but not Bcrp-knockout mice, supporting specificity for Bcrp inhibition (Merino et al, 2010).…”

Potential anticancer properties of bioactive compounds of Gymnema sylvestre and its biofunctionalized silver nanoparticles

“…The potent anticancer activity of G. sylvestre against the human lung adenocarcinoma cell lines (A549) and human breast carcinoma cell lines (MCF7) using alcoholic extracts of the herb has been reported by Srikant et al 21 Also, Amaki et al 22 reported the inhibition of the breast cancer resistance protein using the alcoholic extract of G. sylvestre.…”

Bioavailability of the Glucuronide and Sulfate Conjugates of Genistein and Daidzein in Breast Cancer Resistance Protein 1 Knockout Mice

“…This corresponds to plasma concentration levels significantly less than the IC 50 value reported for the anticancer and other beneficial in vitro effects described for these isoflavones (Imai al., 2004;de Kok et al, 2008). For example, Tamaki et al (2010) obtained genistein and daidzein IC 50 values of 0.24 and 2.4 M, respectively. However, the inhibitory potency of daidzein decreased 100-fold by 7-glucuronidation and was virtually unaffected by 4Ј-sulfation because they obtain an IC 50 of 426 M for daidzein 7-glucuronide and IC 50 of 3.89 M for daidzein-4Ј-sulfate.…”