Pharmacokinetics of [14C]Genistein in the Rat: Gender-Related Differences, Potential Mechanisms of Biological Action, and Implications for Human Health

doi:10.1006/taap.2000.8902

Toxicology and Applied Pharmacology

Volume 164, Issue 2, 15 April 2000, Pages 206-215

https://doi.org/10.1006/taap.2000.8902 Get rights and content

Abstract

Mass balance, plasma pharmacokinetics, tissue distribution, and metabolism of [¹⁴C]genistein were investigated in male and female rats (n = 5) following an oral dose of [¹⁴C]genistein (4 mg kg⁻¹) to determine potential sites and mechanisms of biological action. Mean total excretion of radioactivity in urine and feces for both sexes was 66 and 33% of the dose respectively at 166 h after administration. Mean and maximal concentrations of radioactivity in plasma were significantly (p < 0.02) higher in male than female rats, with half-lives of 12.4 and 8.5 h, respectively. The concentration of radioactivity was significantly (p < 0.002) higher in liver from females than males and in reproductive (vagina, uterus, ovary, and prostate) compared with other peripheral organs. Analysis of plasma extracts by radio-HPLC-MS indicated that the predominant metabolites were genistein glucuronides, 4-hydroxyphenyl-2-propionic acid, and trace amounts of parent compound (<5%). Radioactive residues in uterus and prostate were predominantly parent compound and 4-hydroxyphenyl-2-propionic acid, respectively. Significantly (p < 0.05) increased retention of [¹⁴C]genistein or metabolites was associated with reproductive organs, such as vagina, uterus, ovary, and prostate, likely to contain relatively high concentrations of estrogen receptors or binding proteins compared with other peripheral tissues. Factors liable to influence bioavailability of biologically active genistein or metabolites, such as dietary intake, warrant further investigation to determine the risks or benefits for different consumer groups of phytoestrogen-containing foods.

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Genistein is an isoflavone molecule with a high affinity for estrogen receptors (ER), which could lead to the mechanism of selective estrogen receptor modulators (SERMs) in breast cancer. Genistein labeling with technetium-99^m can be a new promising strategy for diagnostic breast cancer. In this research, we evaluate the physicochemical characteristics of the [^99mTc]Tc-genistein complex and describe the optimal labeling method parameters. We also calculated density functional theory to study the stability constants to support complex formation analysis (DFT).
The genistein was directly labeled with ^99mTc, and its stability as well as its potential for usage as a radiotracer were all investigated. DFT calculations with thermodynamic cycles to determine chemical coordination models and calculate thermodynamic constants of complex more accurately.
The radiochemical purity of [^99mTc]Tc-genistein showed a high yield of 93.25% ± 0.30% and had good physicochemical properties. The stability of the Tc(IV)-genistein complex was confirmed by DFT calculations at a value of 99.0822.
As a result, [^99mTc]Tc-genistein could be a potential radiotracer kit for SPECT imaging of breast cancer.
Oral genistein-loaded phytosomes with enhanced hepatic uptake, residence and improved therapeutic efficacy against hepatocellular carcinoma
2021, International Journal of Pharmaceutics
Genistein (Gen) is one of the most potent soy isoflavones used for hepatocellular carcinoma (HCC) treatment. Low aqueous solubility and first-pass metabolism are the main obstacles resulting in low Gen oral bioavailability. The current study aims to introduce phytosomes as an approach to improve Gen solubility, protect it from metabolism by complexation with phospholipids (PL), and get used to PL in Gen lymphatic delivery. Different forms of PL namely: Lipiod® S100, Phosal® 53 MCT, and Phosal®75 SA were used in phytosomes preparation GP, GPM, and GPL respectively. The effect of formulation components on Gen absorption, metabolism, and liver accumulation was evaluated following oral administration to rats. Cytotoxicity and cellular uptake studies were applied on HepG2 cells and in-vivo anti-tumor studies were applied to the DEN-mice model. Results revealed that GP and GPL remarkably accumulated Gen aglycone in hepatic cells and minimized the metabolic effect on Gen. They significantly increased the intracellular accumulation of Gen in its complex form in HepG2 cells. Their cytotoxicity is time-dependent according to the complex stability. The enhanced in-vivo anti-tumor effect was observed for GP and GPL compared to Gen suspension on DEN-induced HCC in mice. In conclusion, Gen-phytosomes can represent a promising approach for liver cancer treatment.
Structure–bioavailability relationship study of genistein derivatives with antiproliferative activity on human cancer cell
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Citation Excerpt :
In vivo bioavailability experiments were performed in female rats because in this sex, genistein is better absorbed. Moreover, females weigh less than males, which is important due to the limited availability of the tested compounds [12]. Genistein derivatives: series Gen, Gen’, Ram, Ram’ [6,7,13] and Ram-C-α/β [8] were synthesized in the Department of Organic Chemistry, Bioorganic Chemistry and Biotechnology, Faculty of Chemistry and in the Biotechnology Centre (Silesian University of Technology, Gliwice, Poland).
The present study assesses the in vitro and in vivo bioavailability of genistein derivatives, hydroxyalkyl- and glycosyl alkyl ethers (glycoconjugates). Studies were carried out using compounds that exhibit higher in vitro antiproliferative activity in comparison with the parent isoflavone.
Based on in vitro experiments using the Parallel Artificial Membrane Permeability Assay (PAMPA) and the Caco-2 cell monolayer permeability model, we found that modification of the isoflavone structure by O-alkylation improved bioavailability in comparison to genistein. Additionally, the structure of the substituent and its position on genistein influenced the type of mechanism involved in the transport of compounds through biological membranes. The PAMPA assay showed that the structure of glycoconjugates had a significant influence on the passive transport of the genistein synthetic derivatives through a biological membrane. Preferentially the glycoconjugates containing O-glycosidic bond were transported and the transport rate decreased as the carbon linker increased. For glycoconjugates, determination of their transport and metabolism through the Caco-2 membrane was not possible due to interaction with the membrane surface, probably by the change of compound structure caused by contact with the cells or degradation in medium.
The intestinal absorption and metabolism of genistein and three derivatives, Ram-3, Ram′-3 and Ram-C-4α (Fig. 1), were tested in vivo in rats. We found that in comparison to genistein, glycoconjugates were metabolized more slowly and to a lesser extent. As part of the in vivo research, we performed analysis of compound levels in plasma samples after enzymatic hydrolysis, but in the collected samples, analytes were not observed. We hypothesize that glycoconjugates compounds bind plasma proteins and were removed from the sample.
In conclusion, we show that O-functionalization of the natural, biologically active isoflavone genistein can affect biological activity, bioavailability, and the rate of compound metabolism. The position of the substituent, the length of the linker and the structure of sugar moieties provides a tool for the optimization of the derivative's biological properties.
Comparative metabolism of two major compounds in Fructus Corni extracts by gut microflora from normal and chronic nephropathy rats in vitro by UPLC-Q-TOF/MS
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Herbal medicines are widely used as therapeutic products in many countries. Fructus Corni, a traditional herb medicine, has been clinically used to cure chronic nephropathy for thousands of years. It could be converted by gut microflora in vivo to shape its pharmacological profiles. Thus, metabolic profiles of major active constituents in Fructus Corni extracts by gut microflora from rats in healthy and nephropathy state were firstly investigated in vitro by ultraperformance liquid chromatography coupled with quadrupole time-of-flight mass spectrometry (UPLC-Q-TOF/MS) in this study. According to the features of protonated ions, five metabolites (M1, M2, M3, M5 and M6) were found and preliminarily authenticated. Intestinal bacteria were capable of converting N0 (loganin) to its aglycone M1 (loganetin). The latter was further hydrogenated to the corresponding M2 (hydrogenated loganetin) and subsequently to M3 (hydrogenated and demethylated loganetin) by demethylation; While M5 (demethylated morronisid aglycone) and M6 (dehydroxylated morronisid aglycone) were identified as the two metabolites of N4 (morronisid) through demethylation and dehydroxylation. Gut microflora from healthy and nephropathy rats could degrade loganin and morronisid to the above metabolites. However, healthy rat intestinal bacteria showed more powerful degradation and much more amounts of M1 and M6 were obtained in their samples. Additionally, this work demonstrated that UPLC-Q-TOF/MS approach connected with MetaboLynx™ analysis software was rapid and reliable for screening and authentication of natural product metabolites.
Bioavailability of flavonoids: The role of cell membrane transporters
2018, Polyphenols: Mechanisms of Action in Human Health and Disease
Dietary flavonoids play an important role in the prevention of diseases related to oxidative stress in living systems. Although much attention has been focused on studying the protective functions of flavonoids, so far only limited biochemical research was done to tackle the fundamental issue of how flavonoids enter cells. Flavonoids have limited bioavailability, and consequently low plasma concentrations. Thus, in order to enter the intracellular compartment of cells in target tissues, flavonoids must exploit specific cell membrane transporter systems. This interaction between flavonoids and the proteins that mediate their transmembrane transport is of critical importance since it affects both the pharmacokinetic and pharmacodynamic properties of the flavonoids. Extensive knowledge of cell membrane transporters is therefore essential to fully understand the mechanisms of flavonoid-mediated protective activity in the cardiovascular, renal, hepatic, and central nervous systems, and also to elucidate flavonoid-drug interactions.
Genistein: Its role in metabolic diseases and cancer
2017, Critical Reviews in Oncology/Hematology
Citation Excerpt :
Nevertheless, additional investigations are necessary in order to define the combined properties of ovariectomy plus genistein on AdipoR expression as well as serum adiponectin levels. Since the key mechanism of genistein involves its interaction with estrogen receptors, gender difference is commonly reported in the clinical investigations of genistein (Coldham and Sauer, 2000; Penza et al., 2006). Female SD rats portray a two times higher oral bioavailability of genistein aglycone (14.6 vs 6.8%) as well as total genistein (110.8 vs 55.2%) as compared to their male counterparts (Coldham and Sauer, 2000).
Genistein is an isoflavone present in soy and is known to have multiple molecular effects, such as the inhibition of inflammation, promotion of apoptosis, and modulation of steroidal hormone receptors and metabolic pathways. Since these molecular effects impact carcinogenesis, cancer propagation, obesity, osteoporosis, and metabolic syndromes, genistein plays an important role in preventing and treating common disorders. The role of genistein has not been adequately evaluated in all these clinical settings. This review summarizes some of the known molecular effects of genistein and its potential role in health maintenance and treatment.

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Regular ArticlePharmacokinetics of [14C]Genistein in the Rat: Gender-Related Differences, Potential Mechanisms of Biological Action, and Implications for Human Health

Abstract

Lancet

J. Biol. Chem.

Am. J. Clin. Nutr.

Clin. Chim. Acta

J. Steroid Biochem. Mol. Biol.

J. Steroid Biochem. Mol. Biol.

J. Nutr.

J. Biol. Chem.

J. Steroid Biochem. Mol. Biol.

J. Nutr.

J. Nutr.

Dietary intervention study to assess estrogenicity of dietary soy among postmenopausal women

J. Clin. Endocrinol. Metab.

HPLC-mass spectrometry analysis of isoflavones

Proc. Soc. Exp. Biol. Med.

Soy isoflavonoids and cancer prevention

Adv. Exp. Med. Biol.

Soybeans inhibit mammary tumours in models of breast cancer

Prog. Clin. Biol. Res.

Various effects of tyrosine kinase inhibitors on avain osteoclastic activity and reduction of bone loss in ovariectomised rats

J. Cell Biochem.

Tissue distribution of estrogen receptors alpha (ER-α) and beta (ER-β) mRNA in the midgestational human fetus

J. Clin. Endocrinol. Metab.

Battle of Hearts and Hormones: The Financial Times 2

Tissue distribution and quantitative analysis of estrogen receptor-α (ERα) and estrogen receptor-β (ERβ) messenger ribonucleic acid in the wild-type and ERα-knockout mouse

Endocrinology

Regular Article
Pharmacokinetics of [¹⁴C]Genistein in the Rat: Gender-Related Differences, Potential Mechanisms of Biological Action, and Implications for Human Health