• BMB Reports
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• v.44 no.7
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• pp.423-434
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• 2011

A female hormone, estrogen, is linked to breast cancer incidence. Estrogens undergo phase I and II metabolism by which they are biotransformed into genotoxic catechol estrogen metabolites and conjugate metabolites are produced for excretion or accumulation. The molecular mechanisms underlying estrogen-mediated mammary carcinogenesis remain unclear. Cell proliferation through activation of estrogen receptor (ER) by its agonist ligands and is clearly considered as one of carcinogenic mechanisms. Recent studies have proposed that reactive oxygen species generated from estrogen or estrogen metabolites are attributed to genotoxic effects and signal transduction through influencing redox sensitive transcription factors resulting in cell transformation, cell cycle, migration, and invasion of the breast cancer. Conjuguation metabolic pathway is thought to protect cells from genotoxic and cytotoxic effects by catechol estrogen metabolites. However, methoxylated catechol estrogens have been shown to induce ER-mediated signaling pathways, implying that conjugation is not a simply detoxification pathway. Dual action of catechol estrogen metabolites in mammary carcinogenesis as the ER-signaling molecules and chemical carcinogen will be discussed in this review.

• Archives of Pharmacal Research
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• v.23 no.5
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• pp.513-517
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• 2000

Enterohepatic recycling of estrogen after oral administration of 1 mg non-radioactive estriol was studied in fourteen women selected as the control subjects and ten infertile women in whom the infertility was appearing to be of endocrine origin. The extent of enterohepatic recycling of estriol ($E_3$) during the early follicular phase of menstrual cycle was assessed by monitoring during 48 h the urinary excretion of its two major metabolites i.e; estriol 16 $\alpha$-glucuronide ($E_3-16$$\alpha-G$) and estriol-3 glucuronide ($E_3$-3-G). The change in urinary level of $E_3$-3-G with respect to ($E_3-16$$\alpha-G$G was considered to reflect the extent of enterohepatic recycling of estriol. Lower values of urinary output of both metabolites in the infertile women as compared with the control subjects and the urinary excretion profile of both metabolites during 48 h after estriol ingestion reveal that the reduced extent of enterohepatic recycling could possibly be one of the factors which contribute towards the incidence of infertility in women.

• Molecules and Cells
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• v.20 no.3
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• pp.378-384
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• 2005

Estrogen metabolites are carcinogenic. The comparative mitogenic activities of $17{\beta}$-estradiol (E2) and four metabolites, 2-hydroxyestradiol (2-OHE2), 4-hydroxyestradiol (4-OHE2), $16{\alpha}$-hydroxyestrone ($16{\alpha}$-OHE1) and 2-methoxyestradiol (2-ME), were determined in estrogen receptor(ER)-positive MCF-7 human breast cancer cells. Each of the E2 metabolites caused proliferation of the MCF-7 cells, but only E2 and $16{\alpha}$-OHE1 induced a greater than 20-fold increases in transcripts of the progesterone receptor (PR) gene, a classical ER-mediated gene. This suggests that the mitogenic action of E2 and $16{\alpha}$-OHE1 could result from their effects on gene expression via the ER. E2 metabolites altered the expression of E2-regulated proteins including heat shock proteins (Hsps). $16{\alpha}$-OHE1 and 2-ME as well as E2 increased levels of Hsp56, Hsp60, $Hsp90{\alpha}$ and Hsp110 transcripts, and the patterns of these inductions resembled that of PR. Hsp56 and Hsp60 protein levels were increased by all the E2 metabolites. Levels of the transcripts of 3 E2-upregulated proteins (XTP3-transactivated protein A, protein disulfide isomerase-associated 4 protein and stathmin 1) and an E2-downregulated protein (aminoacylase 1) were also affected by the E2 metabolites. These results suggest that the altered expression of Hsps (especially Hsp56 and Hsp60) by E2 metabolites such as E2, $16{\alpha}$-OHE1 and 2-ME could be closely linked to their mitogenic action.

• Biomedical Science Letters
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• v.24 no.3
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• pp.143-149
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• 2018

Excessive exposure to estrogens is the most important risk factor for the development of hormone-sensitive cancers, especially breast cancer. Estrogen stimulates the expression of genes and proteins involved in cell proliferation by binding to estrogen receptor (ER). Another possible mechanism of ER-independent carcinogenicity of estrogens is based on the hydroxylation of estradiol resulting in the formation of catechol estrogens. Catechol estrogen 4-hydroxyestradiol ($4-OHE_2$) is further oxidized to catechol estrogen-3,4-quinones, the major carcinogenic metabolites of estrogens. Evidence increasingly supports the critical role of $4-OHE_2$ in hormonal carcinogenesis via DNA adduct formation or production of reactive oxygen species, which finally contribute to the transformation of normal mammary epithelial cells and the enhanced growth of breast cancer cells. It is also reported that the level of $4-OHE_2$ or its quinones is highly up-regulated in urine or tissues of breast cancer patients. Thus, we highlight the oncogenic roles of $4-OHE_2$ in catechol estrogen-induced breast carcinogenesis.

• Biomedical Science Letters
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• v.25 no.1
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• pp.1-6
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• 2019

The hydroxylation of estradiol results in the formation of catechol estrogens such as 2-hydroxyestradiol ($2-OHE_2$) and 4-hydroxyestradiol ($4-OHE_2$). These catechol estrogens are further oxidized to quinone metabolites by peroxidases or cytochrome P450 (CYP450) enzymes. Catechol estrogens contribute to hormone-induced carcinogenesis by generating DNA adducts or reactive oxygen species (ROS). Interestingly, many of the natural products found in living organisms have been reported to show protective effects against carcinogenesis induced by catechol estrogens. Although some compounds have been reported to increase the activity of catechol estrogens via oxidation to quinone metabolites, many natural products decreased the activity of catechol estrogens by inhibiting DNA adduct formation, ROS production, or oxidative cell damage. Here we focus specifically on the chemopreventive effects of these natural compounds against carcinogenesis induced by catechol estrogens.

• Proceedings of the PSK Conference
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• 2003.10b
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• pp.131.1-131.1
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• 2003

Phytoestrogens are naturally occurring compounds derived from plants. Structurally, some phytoestrogens resemble endogenous estrogen of humans and animals. Phytoestrogens exhibit estrogen agonist/antagonist properties and have many biological effects such as prevention of hormone-dependent breast cancer, anti-oxidative activity, inhibition of tyrosine kinase activities and inhibition of angiogenesis. In this study we investigated whether biochanin A, a phytoestrogen, and its metabolites such genistein, p-ethylphenol and phenolic aic affect IL-4 production in EL-4 thymoma cell-line and primary lymph node cells. (omitted)

• Korean Journal of Biological Psychiatry
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• v.6 no.2
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• pp.209-218
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• 1999

Objectives : The aims of this study were to discriminate the clinical differences, to measure the estrogen and homovanillic acid levels, to evaluate a correlation between estrogen and homovanillic acid, and to identify an association of cognitive deficit with estrogen and homovanillic acid among male and female schizophrenics. Methods : In addition to the structured interviews, the plasma estrogen levels by radioimmunoassay and the homovanillic acid levels by HPLC were measured in 20 male and 21 female schizophrenics as well as 10 healthy male and 9 female controls. Results : 1) The plasma estrogen levels were higher in females than males, and significantly higher in female schizophenics than female controls. The homovanillic acid levels were higher in female schizophrenics than female controls, and were lower in male schizophrenics than male controls. 2) The onset age seemed to be earlier in male schizophrenics, and the frequency of admission, duration of antipsychotic drug administration, dosage of antipsychotics and duration of illnesses were more in males. The estrogen and homovanillic acid levels were significantly higher in female schizophrenics. 3) The estrogen levels had a significant positive correlation with sex, age and onset age, while the homovanillic acid levels did with sex. However, estrogen were not correlated with homovanillic acid levels. 4) The estrogen and homovanillic acid levels were not significantly different between male and female schizophrenics with cognitive deficits. In the schizophrenic patients without cognitive deficits, the estrogen levels were significantly higher in females, while there were no significant sex differences in homovanillic acid. 5) In the male and female schizophrenics predominantly with negative symptoms, there were no significant differences in estrogen and homovanillic acid levels. In those predominantly with positive symptoms, the estrogen levels were significantly higher in females, while there were no sex differences in homovanillic acid levels. 6) In schizophrenics with undifferentiated subtype, the estrogen and homovanillic acid levels were significantly higher in females. In those with paranoid or disorganized subtypes, the estrogen levels were significantly higher in females, while there were no sex differences in the homovanillic acid levels. 7) The mean values of PANSS-negative, PANSS-total, PANSS-CF, MMSE-K and estrogen levels were significantly higher in male schizophrenics with cognitive deficits. The mean values of illness duration, CGI, PANSS-positive, PANSS-negative, PANSS-total, PANSS-CF and MMSE-K were significantly higher in female schizophrenics with cognitive deficits. 8) The variables which showed significant correlation with cognitive deficits were PANSS-negative, PANSS-total, PANSS-CF, MMSE-K and estrogen levels in male schizophrenics. The variables which showed significant correlation with cognitive deficits were subtypes, onset age, illness durataion, CGI, PANSS-positive, PANSS-negative, PANSS-total, PANMSS-CF and MMSE-K in female schizophrenics. The estrogen levels were significantly correlated with admission frequencies, history of antipsychotic administration, duration of antipsychotic administration and cognitive deficits in male schizophrenics, while age were not correlated with in females. The homovanillic acid levels had a significant correlation with subtypes and onset age in male schizophrenics, while there were no correlation among variables in females. Conclusions : Although the plasma concentrations of estrogen and homovanillic acid in female schizophrenics were significantly higher than males, we could not find an association between them. Furthermore, the various factors affecting on the cognitive deficits, estrogen and homovanillic acid levels seemed to be somewhat different according to sex.

• CELLMED
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• v.13 no.14
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• pp.15.1-15.15
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• 2023

Background and objective: A new formular CPC22 consists of Cynanchum wilfordii root, Pueraria thomsonii flower, and Citrus unshiu peel and has been developed to improve the postmenopausal symptoms. The research intended to evaluate whether CPC22 would regulate bone loss, hot flashes, and dysregulated lipid metabolism in ovariectomized (OVX) postmenopausal mice. Method: The OVX mice were orally administered with CPC22 daily for 7 weeks. Results: CPC22 regulated OVX-induced bon loss by enhancing serum osteoprotegerin, alkaline phosphatase, and osteocalcin levels and diminishing serum receptor-activator of the NF-κB ligand (RANKL), collagen type 1 cross-linked N-telopeptide, and tartrate-resistant acid phosphatase levels. As a result of CPC22 treatment, notable decreases in tail skin temperature and rectal temperature were observed, along with diminishment in hypothalamic RANKL and monoamine oxidase A levels and enhancement in hypothalamic serotonin (5-HT), norepinephrine, dopamine, 5-HT2A, and estrogen receptor-β levels. CPC22 enhanced levels of serum estrogen and diminished levels of serum follicle-stimulating hormone and luteinizing hormone. CPC22 regulated levels of serum lipid metabolites, including total cholesterol, triglycerides, low-density lipoprotein cholesterol, and high-density lipoprotein cholesterol. Furthermore, CPC22 diminished levels of serum blood urea nitrogen, creatine kinase, alanine transaminase, aspartate aminotransferase, and lactate dehydrogenase and restored vaginal dryness without affecting uterus atrophy index and vagina weights. Conclusion: Therefore, these results indicated that CPC22 improves OVX-induced bone loss, hot flashes, and dysregulated lipid metabolism by compensating for estrogen deficiency without side effects, suggesting that CPC22 may be used for the prevention and treatment of post menopause.

• Analytical Science and Technology
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• v.11 no.5
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• pp.374-385
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• 1998

Phytoestrogens are biologically active compounds derived from plants foods. It had been suggested that phytoestrogens, by inhibiting aromatase in peripheral and/or cancer cells and lowering estrogen levels, may play a protective role as antipromotional compounds during growth of estrogen-dependent cancers. Therefore, simultaneous analysis of estrogens and phytoestrogens is necessary to elucidate the possible involvement of phytoestrogens in estrogen metabolism. In this view, we developed a simple and reproducible procedure to quantitatively determine estrogen and phytoestrogen metabolites. The proposed method consisted of solid phase extraction using preconditioned Serdolit AD-2 resin, enzyme hydrolysis with ${\beta}$-glucuronidase/arylsulfatase from Helix pomatia, liquid-liquid extraction and TMS-ether derivatization. And the final determination was carried out by gas chromatography/mass spectrometry (GC/MS) in selected ion monitoring mode (SIM). The precision and accuracy of this method was evaluated through within-a-day and day-to-day test. Recovery range and detection limit were 71.96~105.66%, 2~4 ng/mL, respectively. Using this method, 17 estrogen and 5 phytoestrogen compositions in urine of normal subjects were analyzed. It was found that amounts and relative distribution of urinary phytoestrigens and estrogens showed different pattern in male and female subjects.

• Proceedings of the Korean Society of Applied Pharmacology
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• 2001.11a
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• pp.112-112
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• 2001

2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) is an environmental toxin that activates the aryl hydrocarbon receptor (AhR) and disrupts multiple endocrine signaling pathways by enhancing ligand metabolism, altering hormone synthesis, down regulating receptor levels, and interfering with gene transcription. And TCDD-mediated gene transactivation via the AhR has been shown to be dependent upon estrogen receptor (ER) expression in human breast cancer cells. In the present study, we have examined the effect of natural estrogen, phytoestrognes and environmental estrogens on the regulation of CYP1A1 gene expression in MCF-7 human breast cancer cell line. that ER and AhR are co-expressed. pCYP1A1 -luc reporter gene was transiently transfected into MCF-7 cells. These cells were treated with various chemicals and then luciferase assay was carried out. 17be1a-estradiol significantly inhibited TCDD stimulated luciferase activity dose dependently and this inhibition was partially recovered by concomitant treatment of tamoxifen. 17beta-estradiol metabolites, 2-hydroxyestradiol and 16alpha-estriol resulted in less potent inhibitory effect than estradiol and synthetic estrogen, diethylstilbestrol (DES) showed no effect on CYP1A1 gene expression. This study demonstrated that estrogen down-regulated TCDD stimulated CYP1A1 expression via ER mediation. And we have found out that several flavonoids such as genistein, kaempferol, daidzein, naringenin, and alkylphenols such as nonylphenol, 4-octylphenol and resveratrol also inhibited TCDD induced CYP1A1 expression like estrogen.