Effect of genistein on the activities of cytochrome P450 3A and P-glycoprotein in Chinese healthy participants

Xiao, Chang-Qiong; Chen, R.; Lin, Jie; Wang, Guanchao; Chen, Y.; Tan, Zhi‐Rong; Zhou, Hong‐Hao

doi:10.3109/00498254.2011.615954

Cited by 31 publications

(27 citation statements)

References 34 publications

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“…Inhibition of detoxifying metabolic enzymes (CYP3A4) and ABC transport proteins, reducing drug efflux, can increase systemic and intracellular levels of taxanes, which increases their bioavailability, but also toxicity and side effects. Inhibition of CYP3A4 activity by genistein has been demonstrated in vitro and in clinical trials and we observed similar effects in our in vitro experiments. We also found considerable inhibition of efflux activity by genistein.…”

Section: Discussionsupporting

confidence: 90%

Lack of combination effects of soy isoflavones and taxane chemotherapy of castration‐resistant prostate cancer

2018

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Background Patients with cancer, including prostate cancer, often use dietary supplements, such as soy or isoflavones, before, during, or after therapy. There is little information about possible interactions between supplements and cancer chemotherapy. There are some reports suggesting enhancement by genistein of taxane chemotherapy for castrate‐resistant prostate cancer (CRPC). Methods We investigated whether physiologically attainable concentrations of soy isoflavones (≤10 μM) interact with taxanes on growth inhibition of CRPC cells in vitro and in vivo in nude mice exposed via the diet, on microtubule disassembly in vitro, and on P‐glycoprotein‐mediated drug efflux in 22Rv1 cells and CYP3A4 activity in microsomes. Results Genistein, daidzein, and equol did not affect growth of VCaP, 22Rv1, C4‐2, and PC‐3 CRPC cells or growth inhibition of these cells by docetaxel and cabazitaxel. These isoflavones did not inhibit microtubule disassembly in vitro or inhibit the microtubule effects of taxanes and genistein did not bind substantially to microtubules. Genistein considerably inhibited P‐glycoprotein‐mediated drug efflux in 22Rv1 cells and CYP3A4 activity in microsomes. However, dietary supplementation with genistein at 250 and 500 ppm did not affect the tumor growth inhibiting effect of docetaxel on 22Rv1 cells xenografted in nude mice. Conclusions Our results with relevant cell models and clinically achievable concentrations of soy isoflavones do not support the notion that genistein or other soy isoflavones can enhance the effects of taxane chemotherapy in CRPC cell and xenograft models. Yet, the inhibitory effects of genistein on drug efflux in 22Rv1 cells and on microsomal CYP3A4 activity raise the possibility that genistein can affect taxane effects on CRPC cells in other circumstances than those we studied, which merits further research.

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Section: Discussionsupporting

confidence: 90%

Lack of combination effects of soy isoflavones and taxane chemotherapy of castration‐resistant prostate cancer

2018

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“…36 On the other hand, there have been studies that showed contradictory results where Gen increased Pgp expression and function at 1 and 10 µM in the hepatocellular carcinoma-derived HepG2 cell line, 37 and 14 days' administration of Gen reduced oral bioavailability of talinolol, a Pgp substrate, in healthy human participants. 38 At any rate, Gen showed a modest induction of Pgp activity at 200 µM in the present study, and this should be considered in the interpretation of the results obtained using Gen. In the case of Cpz, Rho uptake was increased by 22%, suggesting modest inhibition of Pgp by Cpz.…”

Section: Discussionmentioning

confidence: 45%

Enhanced anticancer activity and intracellular uptake of paclitaxel-containing solid lipid nanoparticles in multidrug-resistant breast cancer cells

Xu¹,

Bae²,

Lee³

2018

IJN

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PurposeThe aim of this study was to show enhanced anticancer activity of paclitaxel (Ptx) incorporated into solid lipid nanoparticles (SLNs) and reveal reversal of multidrug resistance (MDR) by SLNs mediated by increased uptake through different entry mechanisms from that in drug-sensitive cells.MethodsAnticancer activity of Ptx incorporated in SLNs (Ptx-SLNs) was measured in the drug-sensitive human breast cancer cell line MCF7 and its MDR variant MCF7/ADR. Cellular uptake of cargo molecules in SLNs was compared using Ptx-SLNs and rhodamine 123-loaded SLNs (Rho-SLNs) in both cell lines. In addition, endocytic uptake was evaluated using genistein (Gen) and chlorpromazine (Cpz) as inhibitors of clathrin- and caveola-mediated endocytosis, respectively.ResultsPtx-SLNs showed remarkably enhanced anticancer activity in MCF7/ADR compared to Ptx delivered in dimethyl sulfoxide (DMSO) and Cremophor EL-based vehicles. SLNs significantly increased intracellular uptake of Ptx and Rho in MCF7/ADR. Western blotting demonstrated that clathrin was expressed in both cell lines, while caveolin 1 was expressed only in MCF7/ADR. In MCF7/ADR, uptake of Ptx-SLNs and Rho-SLNs was reduced by Gen, while there was no change by Cpz, suggesting the involvement of caveola-mediated endocytosis. Size reduction of Rho-SLNs through high-pressure homogenization (Rho-SLNs) appeared to cause a shift of the endocytosis mechanism from a clathrin-independent pathway to a clathrin-dependent one. In contrast to MCF7/ADR, the uptake of SLNs into MCF7 was not changed by Gen or Cpz, suggesting involvement of clathrin- and caveola-independent mechanism for the entry of SLNs.ConclusionMDR was reversed by incorporating drug into SLNs, and the reversal was mediated by increased uptake of SLNs evading efflux pumps in MDR cells. The enhanced uptake could also be due to the use of different endocytosis pathways by SLNs in MDR cells from drug-sensitive cancer cells.

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“…In contrast, although genistein diets also had no effect on expression of rat hepatic CYP3A2, both dietary daidzein and phytochemical stripped soy protein diets significantly increased expression of CYP3A2 mRNA, CYP3A2 protein and testosterone 6β-hydroxylase activity (Ronis et al 2006b). A recent clinical study in healthy Chinese volunteers receiving genistein for 14 days reported significant increases in clearance of CYP3A substrates midazolam and talinolol suggesting that consumption of genistein supplements may result in a modest increase in CYP3A in humans (Xiao et al 2012). …”

Section: Isoflavones Pxr-signaling and Cyp3a Enzymesmentioning

confidence: 99%

Effects of soy containing diet and isoflavones on cytochrome P450 enzyme expression and activity

Ronis¹

2016

Drug Metabolism Reviews

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Cytochrome P450s (CYP) plays an important role in metabolism and clearance of most clinically utilized drugs and other xenobiotics. They are important in metabolism of endogenous compounds including fatty acids, sterols, steroids and lipid soluble vitamins. Dietary factors such as phytochemicals are capable of affecting CYP expression and activity which may be important in diet-drug interactions and in development of fatty liver disease, cardiovascular disease and cancer. One important diet-CYP interaction is with diets containing plant proteins, particularly soy protein. Soy diets are traditionally consumed in Asian countries and are linked to lower incidence of several cancers and of cardiovascular disease in Asian populations. Soy is also an important protein source in vegetarian and vegan diets and the sole protein source in soy infant formulas. Recent studies suggest that consumption of soy can inhibit induction of CY1 enzymes by polycyclic aromatic hydrocarbons which may contribute to cancer prevention. In addition, there is data to suggest that soy components promiscuously activate several nuclear receptors including PXR, PPAR and LXR resulting in increased expression of CYP3As, CYP4As and CYPs involved in metabolism of cholesterol to bile acids. Such soy-CYP interactions may alter drug pharmacokinetics and therapeutic efficacy and be associated with improved lipid homeostasis and reduced risk of cardiovascular disease. The current review summarizes results from in vitro; in vivo and clinical studies of soy-CYP interactions and examines the evidence linking the effects of soy diets on CYP expression to isoflavone phytoestrogens, particularly genistein and daidzein which are associated with soy protein.

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Effect of genistein on the activities of cytochrome P450 3A and P-glycoprotein in Chinese healthy participants

Cited by 31 publications

References 34 publications

Lack of combination effects of soy isoflavones and taxane chemotherapy of castration‐resistant prostate cancer

Lack of combination effects of soy isoflavones and taxane chemotherapy of castration‐resistant prostate cancer

Enhanced anticancer activity and intracellular uptake of paclitaxel-containing solid lipid nanoparticles in multidrug-resistant breast cancer cells

Effects of soy containing diet and isoflavones on cytochrome P450 enzyme expression and activity

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