Genistein genotoxicity: Critical considerations of in vitro exposure dose

Klein, Catherine B.; King, Audrey A.

doi:10.1016/j.taap.2007.06.022

Cited by 113 publications

(85 citation statements)

References 76 publications

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“…This is consistent with our current findings of increased DNA in mammary parenchymal tissue and a tendency for lower fat content. Although there have been reports in the literature of genotoxic effects of genistein, these have been restricted to in vitro studies utilizing pharmacological concentrations of genistein that exceeded 5 mM (Klein and King, 2007). Evaluation of data from this study does not support a genotoxic effect of genistein.…”

Section: Discussionmentioning

confidence: 55%

Dietary genistein stimulates mammary hyperplasia in gilts

Farmer

Palin

Gilani

et al. 2010

Animal

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The possible role of the phytoestrogen genistein on prepubertal development of mammary glands, hormonal status and bone resorption was investigated in gilts. Forty-five gilts were fed a control diet containing soya (CTLS, n 5 15), a control diet without soya (CTL0, n 5 15) or the CTLS diet supplemented with 2.3 g of genistein daily (GEN, n 5 15) from 90 days of age until slaughter (day 183 6 1). Both basal diets were isonitrogenous and isocaloric. Jugular blood samples were obtained on days 89 and 176 to determine concentrations of isoflavone metabolites (on day 176 only), prolactin, estradiol, progesterone, insulin-like growth factor 1 (IGF1), and N-telopeptide of type I collagen (NTx; on day 176 only). At slaughter, mammary glands were excised, parenchymal and extraparenchymal tissues were dissected, and composition of parenchymal tissue (protein, fat, dry matter (DM), DNA) was determined. Histochemical analyses of mammary parenchyma were performed. Dietary genistein increased parenchymal protein (P , 0.05) while decreasing DM (P , 0.05) and tending to lower fat content compared with the CTLS, but not the CTL0, diet. There was more parenchymal DNA (1.26 v. 0.92 mg/g, P , 0.05) in GEN than CTLS gilts, likely reflecting an increase in the quantity of mammary epithelial cells. Circulating concentrations of genistein were increased in GEN gilts (P , 0.001) but concentrations of hormones or NTx (indicator of bone collagen resorption) were not affected by GEN (P . 0.1). Percentage of estradiol receptor alpha (ERa)-positive epithelial cells was lower (P , 0.05) in GEN than CTLS gilts, whereas 5-bromo-2 0 -deoxyuridine labeling index was unaltered (P . 0.1). Transcript levels for ERa, ERb, IGF1, epidermal growth factor (EGF), epidermal growth factor receptor and transforming growth factor alpha were not altered by treatments. Supplementation of the diet with genistein during the growing phase in gilts, therefore, led to hyperplasia of mammary parenchymal tissue after puberty; yet, even though circulating genistein was increased, this was not accompanied by changes in mammary expression of selected genes or circulating hormone levels.

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Section: Discussionmentioning

confidence: 55%

Dietary genistein stimulates mammary hyperplasia in gilts

Farmer

Palin

Gilani

et al. 2010

Animal

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“…Genistein is a natural soy isoflavone with excellent bioavailability that has both antioxidant and antiproliferative properties (16,40,41). Both oxidative stress and excessive proliferation have been postulated to result in genomic instability in HSCs.…”

Section: Discussionmentioning

confidence: 99%

“…In the current study, we used a dose of genistein that results in serum levels that can easily be obtained through oral supplementation (16,45). At this dosage, genistein partially blocked the G-CSF-induced expansion of LSK cells and significantly reduced pH2AX levels in this population.…”

Section: Discussionmentioning

confidence: 99%

Genistein Protects Hematopoietic Stem Cells against G-CSF–Induced DNA Damage

Souza

Silva

Calloway

et al. 2014

Cancer Prevention Research

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Granulocyte colony-stimulating factor (G-CSF) has been used to treat neutropenia in various clinical settings. Although clearly beneficial, there are concerns that the chronic use of G-CSF in certain conditions increases the risk of myelodysplastic syndrome (MDS) and/or acute myeloid leukemia (AML). The most striking example is in severe congenital neutropenia (SCN). Patients with SCN develop MDS/AML at a high rate that is directly correlated to the cumulative lifetime dosage of G-CSF. Myelodysplastic syndrome and AML that arise in these settings are commonly associated with chromosomal deletions. We have demonstrated in this study that chronic G-CSF treatment in mice results in expansion of the hematopoietic stem cell (HSC) population. In addition, primitive hematopoietic progenitors from G-CSF-treated mice show evidence of DNA damage as demonstrated by an increase in double-strand breaks and recurrent chromosomal deletions. Concurrent treatment with genistein, a natural soy isoflavone, limits DNA damage in this population. The protective effect of genistein seems to be related to its preferential inhibition of G-CSFinduced proliferation of HSCs. Importantly, genistein does not impair G-CSF-induced proliferation of committed hematopoietic progenitors, nor diminishes neutrophil production. The protective effect of genistein was accomplished with plasma levels that are attainable through dietary supplementation. Cancer Prev Res; 7(5); 534-44. Ó2014 AACR.

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“…To ensure sink conditions, the total amount of GEN in the donor compartment was 40 µg (200 µL of a sample containing 0.2 mg/ mL of GEN). The available diffusion area between receptor and donor compartments was 1.86 cm 2 . Stirring rate and temperature were kept, respectively, at 300 rpm and 37°C.…”

Section: Methodsmentioning

confidence: 99%

Development and Validation of a Simple and Rapid Liquid Chromatography Method for the Determination of Genistein in Skin Permeation Studies

Maione-Silva

Rocha

Oliveira

et al. 2012

Biological & Pharmaceutical Bulletin

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Genistein (GEN) has potential advantages for topical skin delivery, but no literature data are available for its quantitation in different skin layers, such as the stratum corneum (SC). Therefore, a simple, rapid, selective and sensitive bioanalytical method was developed and validated for GEN quantitation in porcine skin samples following in vitro permeation studies. GEN was assayed by HPLC with UV-Vis detection (270 nm) using 0.5% acetic acid in water-n-propanol-acetonitrile (50 : 2 : 48, v/v/v) as mobile phase (flowrate of 1.0 mL/min). Specificity was demonstrated since endogenous skin components did not interfere with GEN peak. Standard analytical curve was linear over the concentration range (0.1-60 µg/mL) and the lower limit of quantitation was determined for different skin layers (100 ng/mL). GEN recovery from skin layers ranged from 95.57 to 97.57%. Permeation studies were carried out using an automated vertical diffusion cell apparatus. No fluctuation on the amount of GEN retained in the SC was observed over time, but increasing amounts of the drug were found in deeper layers of the skin. The method was reliable and reproducible for the quantitation GEN in skin samples enabling the determination of the cutaneous penetration profile of this drug in permeation experiments.Key words genistein; HPLC quantitation; bioanalytical validation; skin layer Genistein (GEN) (Fig. 1) is the main isoflavone found in soybeans with several beneficial effects in cardiovascular diseases, osteoporosis and postmenopausal syndrome. Potential advantages of GEN have been reported in different types of cancer, such as breast and prostate, as well as skin cancer. 1) GEN acts in carcinogenesis through different mechanisms such as induction of differentiation, inhibition of topoisomerase II, protein tyrosine kinase activity and angiogenesis. 1,2)Skin cancer arises predominantly from cells located within the epidermis.3) Thus, to reach skin malignancies and achieve therapeutic benefits, antitumoral drugs, such as GEN, have to penetrate the stratum corneum and reach deeper layers of the epidermis. 4) In general, topical administration is a challenge in pharmaceutics. 5) Regardless, previous studies have demonstrated GEN's viability for topical 6) and transdermal permeation from different kinds of vehicles.7) Thus, with the purpose of conducting percutaneous permeation studies, the quantitative determination of the drug in the skin is necessary in order to evaluate the efficiency of the proposed formulations. 8)Due to the complexity of the skin matrices and the need to quantify low levels of the drug in the epidermis, 9) a highly selective analytical tool is required, since most samples usually contain several endogenous components of the skin. In addition, the analytical method must present enough sensitivity, due to possible very low concentrations of the drug present in each skin layer. 10) Considering the complexity and heterogeneity of the skin tissue, an effective extraction procedure to completely recover the analyte from the ...

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Genistein genotoxicity: Critical considerations of in vitro exposure dose

Cited by 113 publications

References 76 publications

Dietary genistein stimulates mammary hyperplasia in gilts

Dietary genistein stimulates mammary hyperplasia in gilts

Genistein Protects Hematopoietic Stem Cells against G-CSF–Induced DNA Damage

Development and Validation of a Simple and Rapid Liquid Chromatography Method for the Determination of Genistein in Skin Permeation Studies

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