Estrogen Biosynthesis Research Articles

CYP19A1 regulates chemoresistance in colorectal cancer through modulation of estrogen biosynthesis and mitochondrial function

Chemoresistance remains a major challenge in the effective treatment of colorectal cancer (CRC), contributing to poor patient outcomes. While the molecular mechanisms underlying chemoresistance are complex and multifaceted, emerging evidence suggests that altered mitochondrial function and hormone signaling play crucial roles. In this study, we investigated the role of CYP19A1, a key enzyme in estrogen biosynthesis, in regulating chemoresistance in CRC. Using a combination of in vitro functional assays, transcriptomic analysis, and clinical data mining, we demonstrate that CYP19A1 expression is significantly upregulated in CRC cells and patient-derived samples compared to normal controls. Mechanistically, we found that CYP19A1 regulates chemoresistance through modulation of mitochondrial function and complex I activity, which is mediated by CYP19A1-dependent estrogen biosynthesis. Notably, targeted inhibition of CYP19A1 and complex I using specific inhibitors effectively reversed the chemoresistance of CRC cells to chemotherapeutic drugs. Moreover, analysis of the TCGA CRC dataset revealed that high CYP19A1 expression correlates with poor overall survival in chemotherapy-treated patients. Taken together, our findings uncover a novel role for CYP19A1 in regulating chemoresistance in CRC through modulation of mitochondrial function and estrogen signaling, and highlight the potential of targeting the CYP19A1/estrogen/complex I axis as a therapeutic strategy to overcome chemoresistance and improve patient outcomes.

Synthesis, Aromatase Inhibition, Cytotoxicity and Molecular Docking Studies of New Fluorinated and Non-fluorinated Thiourea Derivatives of Desloratadine.

Aromatase inhibitors are among the most effective treatment of the breast cancer. Aromatase catalyzes estrogen biosynthesis, which is a long-term cause of breast cancer. Current study describes the synthesis, purification of 26 new fluorinated and non-fluorinated thiourea derivatives of desloratadine (5), and their aromatase inhibition activity, cytotoxicity against cancer cell line (MDA-MB-231). Compounds 7v and 7l exhibited a significant anti-aromatase activity, while compounds 7a, 7g-h, 7m and 7u were also significant active against MDA-MB-231 cell line. Furthermore, the molecular docking studies revealed that active compounds form key interactions with the crucial amino acid of aromatase active site including TRP224, LEU477, CYS437, ALA438, MET374, ARG115, ILE305, and PHE221, which are responsible for the binding interaction of aromatase. All analogues were new, except 7b and 7k and also lacked cytotoxicity BJ human fibroblasts, with the exception of 5 and 7x. This selectivity makes this series particularly interesting for further studies.

Aromatase as a novel target of parabens in human and rat placentas: 3D-quantitative structure-activity relationship and docking analysis

Aromatase (CYP19A1), a pivotal enzyme in the biosynthesis of estradiol from testosterone, is predominantly expressed in reproductive tissues including placentas. This study investigated the effects of paraben acid and nine parabens on the activity of human and rat CYP19A1 using microsomes derived from human and rat placentas and on estradiol secretion in human choriocarcinoma BeWo cells. The results showed that propyl, butyl, hexyl, heptyl, and nonyl parabens significantly inhibited human CYP19A1 activity, with IC50 values of 66.37, 61.08, 55.65, 48.26, and 27.24 μM, respectively. In BeWo cells, these parabens notably diminished estradiol secretion at concentrations of 100 μM. Similarly, rat CYP19A1 was inhibited by these parabens, with IC50 values of 98.07, 70.10, 41.30, 27.93, and 6.33 μM for propyl, butyl, hexyl, heptyl, and nonyl parabens, respectively. Kinetic analysis identified these compounds as mixed inhibitors. Bivariate correlation analysis revealed a negative correlation between the partition coefficient value, molecular weight, the number of carbon atoms in the alcohol moiety, as well as heavy atom number and IC50 values. Three-dimensional quantitative structure-activity relationship analysis highlighted the critical role of hydrophobic regions in determining inhibitory potency. Docking studies suggested that parabens interact with the heme-iron binding site of both human and rat CYP19A1. This study elucidates the inhibitory effects of various parabens on CYP19A1 and their binding mechanisms, thereby providing a deeper understanding of their potential impact on estrogen biosynthesis.

Qualitative and Quantitative Analysis of Stigmasterol from Iraqi Calendula officinalis

Calendula officinalis L. (Asteraceae) plant origin from Mediterranean countries, and in addition to the beauty of its flowers they also have important medicinal properties in the healing of many illnesses particularly skin issues. C. officinalis in the world was reported and assessed as a medicinal plant, like British pharmacopoeia (BP), European pharmacopoeia (EU), WHO and PDR. Calendula officinalis Linn. Contains 0.4% of flavonoids as minimum, calculated as Hyperoside of dried herbal substance according to British pharmacopeia (2). The Chemical Constituents are: Triterpene saponins, Triterpene (Stigmasterol), Flavonoids: isorhamnetin glycosides and quercetin glycosides, Coumarins: umbelliferon, scopoletin and aesculetin, Carotenoids: mainly zeaxanthin and Lutein (5). Stigmasterol is an essential ingredient that has been isolated from plants. Stigmasterol considered a progesterone precursor and serves as an intermediate in corticoids, androgens estrogens biosynthesis (10) and vitamin D3 synthesis (3). Stigmasterol is a triterpenes C30-derive phytosterol, naturally happening C28 and C29 carbon steroid alcohols that is similar to cholesterol in structure as well as biological activity (4).in this study Stigmasterol was identified by TLC, Mass analysis. Structure elucidation was performed using, FTIR and Mass analysis. The quantity of Stigmasterol was measured in the Iraqi plant.

Potential role of solid lipid curcumin particle (SLCP) as estrogen replacement therapy in mitigating TDP-43-related neuropathy in the mouse model of ALS disease

BackgroundAmyotrophic lateral sclerosis (ALS) was first identified in 1869, but it wasn't until the 2014 Ice Bucket Challenge that widespread attention was drawn to the disease. Since then, substantial research has been dedicated to developing treatments for ALS. Despite this, only three drugs - riluzole, edaravone and AMX0035, have been approved for clinical use, and they can only temporarily alleviate mild symptoms without significant disease modification or cure. Therefore, there remains a critical unmet need to identify disease modifying or curative therapies for ALS. The higher incidence and more severe progression of ALS and FTLD (frontotemporal lobar degeneration) observed in men and postmenopausal woman compared to young women suggests that sex hormones may significantly influence disease onset and progression. In both animal models and human clinical studies, 17β estradiol (E2) has been shown to delay and improve the outcomes of many neurodegenerative diseases. Here, we examined the role of TDP-43 in the regulation of estrogen-related enzymes, CYP19A1 and CYP3A4. In addition, we examined the impact of curcumin on the regulation of estrogen E2 levels and TDP-43-associated neuropathy as a potential therapeutic strategy for the treatment of FTLD and ALS. MethodsPrp-TDP-43A315T mice was used as a model of ALS/FTLD to examine the expression patterns of E2 and its biosynthesis and degradation enzymes, CYP19A1 and CYP3A4. Moreover, the molecular mechanisms and the potency of solid lipid curcumin particles (SLCP) as an E2 replacement therapy for TDP-43 associated neuropathy was analyzed. We further examined the survival rates and the pathological TDP43 patterns in female and male Prp-TDP-43A315T mice administrated with or without SLCP. In addition, the changed expression levels of enzymes corresponding to E2 biosynthesis and degradation in the spinal cord of female and male Prp-TDP-43A315T mice with or without SLCP were determined. ResultsWe found that in addition to E2, the expression patterns of CYP19A1 and CYP3A4 proteins differed between Prp-TDP-43A315T mice compared to wild-type control, suggesting that toxic phosphorylated TDP43 oligomers may disrupt the balance between CYP19A1 and CYP3A4 expression, leading to reduced estrogen biosynthesis and accelerated degradation. In addition, we found that oral administration of SLCP prolonged the survival rates in female Prp-TDP-43A315T mice and significantly reduced the pathological insoluble phosphorylated TDP-43 species. Furthermore, SLCP attenuated disease progression associated with TDP-43-related neuropathies through modulating estrogen biosynthesis and the activity of CYP450 enzymes. ConclusionsOur results showed that Prp-TDP-43A315T mice exhibit altered estradiol levels. Moreover, we demonstrated the efficacy of SLCP as an estrogen replacement therapy in mitigating TDP-43-associated disease progression and pathogenesis. These findings suggest that SLCP could be a promising strategy to induce E2 expression for the treatment of ALS and FTLD.

Discovery of potential 1,2,4-triazole derivatives as aromatase inhibitors for breast cancer: pharmacophore modelling, virtual screening, docking, ADMET and MD simulation

ABSTRACT Hormone receptor (HR)-positive breast cancer represents tumours that express estrogen and/or progesterone enzymes, which play a crucial role in the growth and proliferation of breast cancer cells. Aromatase inhibitors (AIs) are drugs that inhibit the enzyme aromatase, involved in the biosynthesis of estrogen and are used for the treatment of HR-positive breast cancer. The USFDA-approved nonsteroidal AIs contain 1,2,4-triazole heterocycle. So, in the present study, we screened seventy-eight 1,2,4-triazole analogues from different literature resources and generated a pharmacophore model. After several validation protocols, Hypo1 was selected as the best model and was used as a 3D query for screening 1,2,4-triazole analogues (15,583) obtained from the CHEMBL database. A dataset containing 320 ligands with estimated activity (IC50< 0.1 µM) was subjected to molecular docking against the aromatase enzyme (PDB ID: 3S79). Amongst the 320 ligands, 30 compounds exhibited better binding energy compared to the standard drug letrozole. These 30 hits were further considered for the design of two novel molecules which were initially assessed for their ADMET properties followed by pharmacophore mapping, docking and molecular dynamics simulation. The in silico findings suggest that both the designed molecules can be considered drug-like candidates for the treatment of breast cancer through aromatase inhibition.

In silico analysis of potential inhibitors for breast cancer targeting 17beta-hydroxysteroid dehydrogenase type 1 (17beta-HSD1) catalyses.

Breast cancer (BC) is still one of the major issues in world health, especially for women, which necessitates innovative therapeutic strategies. In this study, we investigated the efficacy of retinoic acid derivatives as inhibitors of 17beta-hydroxysteroid dehydrogenase type 1 (17beta-HSD1), which plays a crucial role in the biosynthesis and metabolism of oestrogen and thereby influences the progression of BC and, the main objective of this investigation is to identify the possible drug candidate against BC through computational drug design approach including PASS prediction, molecular docking, ADMET profiling, molecular dynamics simulations (MD) and density functional theory (DFT) calculations. The result has reported that total eight derivatives with high binding affinity and promising pharmacokinetic properties among 115 derivatives. In particular, ligands 04 and 07 exhibited a higher binding affinity with values of -9.9 kcal/mol and -9.1 kcal/mol, respectively, than the standard drug epirubicin hydrochloride, which had a binding affinity of -8.2 kcal/mol. The stability of the ligand-protein complexes was further confirmed by MD simulations over a 100-ns trajectory, which included assessments of hydrogen bonds, root mean square deviation (RMSD), root mean square Fluctuation (RMSF), dynamic cross-correlation matric (DCCM) and principal component analysis. The study emphasizes the need for experimental validation to confirm the therapeutic utility of these compounds. This study enhances the computational search for new BC drugs and establishes a solid foundation for subsequent experimental and clinical research.

Steroid sulfatase and sulfotransferases in the estrogen and androgen action of gynecological cancers: current status and perspectives.

Sulfatase (STS) and sulfotransferases (SULT) have important role in the biosynthesis and action of steroid hormones. STS catalyzes the hydrolysis of estrone-sulfate (E1-S) and dehydroepiandrosterone-sulfate (DHEA-S), while sulfotransferases catalyze the reverse reaction and require 3-phosphoadenosine-5-phosphosulfate as a sulfate donor. These enzymes control the concentration of active estrogens and androgens in peripheral tissues. Aberant expression of STS and SULT genes has been found in both, benign hormone-dependent diseases and hormone-dependent cancers. The aim of this review is to present the current knowledge on the role of STS and SULT in gynecological cancers, endometrial (EC) and ovarian cancer (OC). EC is the most common and OC the most lethal gynecological cancer. These cancers primarily affect postmenopausal women and therefore rely on the local production of steroid hormones from inactive precursors, either DHEA-S or E1-S. Following cellular uptake by organic anion transporting polypeptides (OATP) or organic anion transporters (OAT), STS and SULT regulate the formation of active estrogens and androgens, thus disturbed balance between STS and SULT can contribute to the onset and progression of cancer. The importance of these enzymes in peripheral estrogen biosynthesis has long been recognized, and this review provides new data on the important role of STS and SULT in the formation and action of androgens, their regulation and inhibition, and their potential as prognostic biomarkers.

Targeting estrogen metabolism in high-grade serous ovarian cancer shows promise to overcome platinum resistance

The high mortality rate due to chemoresistance in patients with high-grade ovarian cancer (HGSOC) emphasizes the urgent need to determine optimal treatment strategies for advanced and recurrent cases. Our study investigates the interplay between estrogens and chemoresistance in HGSOC and shows clear differences between platinum-sensitive and -resistant tumors. Through comprehensive transcriptome analyzes, we uncover differences in the expression of genes of estrogen biosynthesis, metabolism, transport and action underlying platinum resistance in different tissues of HGSOC subtypes and in six HGSOC cell lines. Furthermore, we identify genes involved in estrogen biosynthesis and metabolism as prognostic biomarkers for HGSOC. Additionally, our study elucidates different patterns of estrogen formation/metabolism and their effects on cell proliferation between six HGSOC cell lines with different platinum sensitivity. These results emphasize the dynamic interplay between estrogens and HGSOC chemoresistance. In particular, targeting the activity of steroid sulfatase (STS) proves to be a promising therapeutic approach with potential efficacy in limiting estrogen-driven cell proliferation. Our study reveals potential prognostic markers as well as identifies novel therapeutic targets that show promise for overcoming resistance and improving treatment outcomes in HGSOC.

The anti-aromatase and anti-estrogenic activity of plant products in the treatment of estrogen receptor-positive breast cancer

Despite being the focal point of decades of research, female breast cancer (BC) continues to be one of the most lethal cancers in the world. Given that 80 % of all diagnosed BC cases are estrogen receptor-positive (ER+) with carcinogenesis driven by estrogen-ERα signalling, current standard of care (SOC) hormone therapies are geared towards modulating the function and expression levels of estrogen and its receptors, ERα and ERβ. Currently, aromatase inhibitors (AIs), selective ER modulators (SERMs) and selective ER degraders (SERDs) are clinically prescribed for the management and treatment of ER+ BC, with the anti-aromatase activity of AIs abrogating estrogen biosynthesis, while the anti-estrogenic SERMs and SERDs antagonise and degrade the ER, respectively. The use of SOC hormone therapies is, however, significantly hampered by the onset of severe side-effects and the development of resistance. Given that numerous studies have reported on the beneficial effects of plant compounds and/or extracts and the multiple pathways through which they target ER+ breast carcinogenesis, recent research has focused on the use of dietary chemopreventive agents for BC management. When combined with SOC treatments, several of these plant components and/or extracts have demonstrated improved efficacy and/or synergistic impact. Moreover, despite a lack of in vivo investigations, plant products are generally reported to have a lower side-effect profile than SOC therapies and are therefore thought to be a safer therapeutic choice. Thus, the current review summarizes the findings from the last five years regarding the anti-aromatase and anti-estrogenic activity of plant products, as well as their synergistic anti-ER+ BC effects in combination with SOC therapies.

Influenza A virus infection disrupts the function of syncytiotrophoblast cells and contributes to adverse pregnancy outcomes.

Pregnancy heightens susceptibility to influenza A virus (IAV) infection, thereby increasing the risk of severe pneumonia and maternal mortality. It also raises the chances of adverse outcomes in offspring, such as fetal growth restriction, preterm birth, miscarriage, and stillbirth in offsprings. However, the underlying mechanisms behind these effects remain largely unknown. Syncytiotrophoblast cells, crucial in forming the placental barrier, nutrient exchange and hormone secretion, have not been extensively studied for their responses to IAV. In our experiment, we used Forskolin-treated BeWo cells to mimic syncytiotrophoblast cells in vitro, and infected them with H1N1, H5N1 and H7N9 virus stains. Our results showed that syncytiotrophoblast cells, with their higher intensity of sialic acid receptors, strongly support IAV infection and replication. Notably, high-dose viral infection and prolonged exposure resulted in a significant decrease in fusion index, as well as gene and protein expression levels associated with trophoblast differentiation, β-human chorionic gonadotropin secretion, estrogen and progesterone biosynthesis, and nutrient transport. In pregnant BALB/c mice infected with the H1N1 virus, we observed significant decreases in trophoblast differentiation and hormone secretion gene expression levels. IAV infection also resulted in preterm labor, fetal growth restriction, and increased maternal and fetal morbidity and mortality. Our findings indicate that IAV infection in syncytiotrophoblastic cells can result in adverse pregnancy outcomes by altering trophoblast differentiation, suppressing of β-hCG secretion, and disrupting placental barrier function.

Genome-wide DNA methylation analysis in blood identifies differentially methylated regions related to polycystic ovary syndrome

Polycystic ovary syndrome (PCOS) is considered a multifactorial disorder caused due to predisposing alleles of various genes and environmental factors which include lifestyle, dietary habits, and exposure to toxicants. Recently the emphasis has shifted to understanding epigenetic alterations due to the poor correlation between genotypes and the clinical profile of women with PCOS. Investigators have been focusing on differential methylation signatures associated with PCOS, therefore, a pilot study was carried out to investigate PCOS-associated differential DNA methylation regions in the population of north India. A cross-sectional study with sixteen participants comprising eight women with PCOS diagnosed under the Rotterdam criterion and eight age and BMI-matched healthy controls. Subjects were classified into four groups based on BMI and two different groups were compared each time making four comparison types in total. Genome-wide DNA methylation in whole blood was evaluated using an Infinium Human Methylation 850k array which identified PCOS-associated differential sites and differential methylation regions (DMRs) with promoter region, and CpG islands considering (p ≤ 0.01) as statistically significant. Multiple significantly associated hypomethylated and hypermethylated loci of genes were identified. Thirty-four hypomethylated and one hundred twenty-six hypermethylated sites of genes were suggested when all the subjects were of low BMI. But when the groups comprised with high BMI, twenty-seven hypomethylated genes and fifty-nine hypermethylated genes were identified. In silico analysis suggests that most of these genes are involved in estrogen biosynthesis, lipid biosynthetic process, and activation of matrix metalloproteinases (MMP). Seven genes that are found common in both of these comparisons are mostly involved in the inflammasome pathway indicated by BioPlanet and Reactome databases. The study provides information about DMRs in the blood tissue which may be investigated further to understand underlying pathogenesis and as therapeutic targets in the future.

Luteolin and its analog luteolin-7-methylether from Leonurus japonicus Houtt suppress aromatase-mediated estrogen biosynthesis to alleviate polycystic ovary syndrome by the inhibition of tumor progression locus 2

Ethnopharmacological relevanceLeonurus japonicus Houtt (L. japonicus, Chinese motherwort), known as Yi Mu Cao which means “good for women”, has long been widely used in China and other Asian countries to alleviate gynecological disorders, often characterized by estrogen dysregulation. It has been used for the treatment of polycystic ovary syndrome (PCOS), a common endocrine disorder in women but the underlying mechanism remains unknown. Aim of the studyThe present study was designed to investigate the effect and mechanism of flavonoid luteolin and its analog luteolin-7-methylether contained in L. japonicus on aromatase, a rate-limiting enzyme that catalyzes the conversion of androgens to estrogens and a drug target to induce ovulation in PCOS patients. Materials and methodsEstrogen biosynthesis in human ovarian granulosa cells was examined using ELISA. Western blots were used to explore the signaling pathways in the regulation of aromatase expression. Transcriptomic analysis was conducted to elucidate the potential mechanisms of action of compounds. Finally, animal models were used to assess the therapeutic potential of these compounds in PCOS. ResultsLuteolin potently inhibited estrogen biosynthesis in human ovarian granulosa cells stimulated by follicle-stimulating hormone. This effect was achieved by decreasing cAMP response element-binding protein (CREB)-mediated expression of aromatase. Mechanistically, luteolin and luteolin-7-methylether targeted tumor progression locus 2 (TPL2) to suppress mitogen-activated protein kinase 3/6 (MKK3/6)-p38 MAPK-CREB pathway signaling. Transcriptional analysis showed that these compounds regulated the expression of different genes, with the MAPK signaling pathway being the most significantly affected. Furthermore, luteolin and luteolin-7-methylether effectively alleviated the symptoms of PCOS in mice. ConclusionsThis study demonstrates a previously unrecognized role of TPL2 in estrogen biosynthesis and suggests that luteolin and luteolin-7-methylether have potential as novel therapeutic agents for the treatment of PCOS. The results provide a foundation for further development of these compounds as effective and safe therapies for women with PCOS.

High Salt Diet Regulates Intrarenal Sex Steroid Biosynthesis Pathway in a Sex-Specific Manner

Hypertension is more prevalent in men than age-matched pre-menopausal women. Sodium (Na+) homeostasis plays a major role in the control of blood pressure. Renal medullary estrogenic signaling promotes Na+ excretion in female, but not male Sprague Dawley (SD) rats implicating estrogen as a potential female-specific natriuretic factor. Recently we showed that the components of estrogen biosynthesis pathway are expressed in rat kidney suggesting the kidneys can produce estrogen locally to invoke this natriuretic response. It is unknown how dietary Na+ impacts biosynthesis of sex hormones. We hypothesize that a high salt (HS) diet enhances intrarenal estrogen biosynthesis pathway, and this enhancement is more pronounced in females compared to males. To test this hypothesis, we harvested the renal cortex from 14 week old male and female SD rats maintained on either a normal salt (NS 0.3% NaCl) or HS (4% NaCl) diet for 5 days. Given that cholesterol is the main precursor of steroid hormones, we measured the mRNA expression of HMG-CoA reductase (HMGCR), the key enzyme for cholesterol synthesis; and the steroidogenic acute regulatory protein (StAR), which transports cholesterol into the mitochondria for steroid commitment. We also assessed the mRNA expression of steroid 5α reductase (SRD5A), which converts testosterone to the non-aromatizable androgen, dihydrotestosterone. Further, we assessed aromatase, the key enzyme in estrogen biosynthesis, via immunohistochemistry. We found that renal HMGCR was more abundant in female compared to male rats maintained on a NS diet (P=0.0467). Increasing dietary salt intake upregulated renal HMGCR expression in male (P=0.0020), but not female rats (NS male; 100.0 ± 26.8 vs. NS female; 235.3 ± 23.2 vs. HS male 294.6 ± 42.0 vs HS female 314.6 ± 21.0 relative expression % NS male n=6-7/group). On a NS diet, renal StAR was more abundant in female compared to male rats (NS male; 100.0 ± 25.3 vs. NS female; 217.2 ± 36.5 relative expression % NS male P=0.0255 n=5-7/group). Increasing dietary salt did not alter expression of StAR in either sex. Similarly, renal SRD5A expression was higher in female compared to male (P=0.0141) rats. In addition, a HS diet increased the expression of SRD5A in female rats (0.0093) and tended to increase SRD5A expression in male (P=0.0849) rats (NS male; 100.0 ± 11.6 vs. NS female; 297.8 ± 37.7 vs. HS male 243.0 ± 39.2 vs HS female 498.8 ± 44.8 relative expression % NS male n=6-7/group). We also revealed that aromatase was expressed at a comparable level in male and female renal cortex, regardless of the diet (NS male; 2.4 ± 0.3 vs. NS female; 2.6 ± 0.3 vs. HS male 2.8 ± 0.3 vs HS female 1.9 ± 0.1 Average intensity x area mM2 n=6-9/group). Together, this data suggests that (i) the female kidney may be more primed for steroid biosynthesis and (ii) there is a sex-specific upregulation of the intrarenal sex steroid biosynthesis pathway in response to increasing dietary salt intake. Additional work is required to investigate the potential role of the kidney in androgen and estrogen production. A better understanding of this steroidogenic pathway could reveal novel sex-specific therapeutics for hypertension. T32DK007569-34 Carl Gottschalk Grant. This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Androgen receptor and estrogen receptor variants in prostate and breast cancers

The androgen receptor (AR) and estrogen receptor alpha (ERα) are steroid receptor transcription factors with critical roles in the development and progression of prostate and breast cancers. Advances in the understanding of mechanisms underlying the ligand-dependent activation of these transcription factors have contributed to the development of small molecule inhibitors that block AR and ERα actions. These inhibitors include competitive antagonists and degraders that directly bind the ligand binding domains of these receptors, luteinizing hormone releasing hormone (LHRH) analogs that suppress gonadal synthesis of testosterone or estrogen, and drugs that block specific enzymes required for biosynthesis of testosterone or estrogen. However, resistance to these therapies is frequent, and is often driven by selection for tumor cells with alterations in the AR or ESR1 genes and/or alternatively spliced AR or ESR1 mRNAs that encode variant forms AR or ERα. While most investigations involving AR have been within the context of prostate cancer, and the majority of investigations involving ERα have been within the context of breast cancer, important roles for AR have been elucidated in breast cancer, and important roles for ERα have been elucidated in prostate cancer. Here, we will discuss the roles of AR and ERα in breast and prostate cancers, outline the effects of gene- and mRNA-level alterations in AR and ESR1 on progression of these diseases, and identify strategies that are being developed to target these alterations therapeutically.

Use of All-Male cyp17a1-Deficient Zebrafish (Danio rerio) for Evaluation of Environmental Estrogens.

Natural and synthetic environmental estrogens (EEs) are widespread and have received extensive attention. Our previous studies demonstrated that depletion of the cytochrome P450 17a1 gene (cyp17a1) leads to all-testis differentiation phenotype in zebrafish and common carp. In the present study, cyp17a1-deficient zebrafish with defective estrogen biosynthesis were used for the evaluation of EEs, as assessed by monitoring vitellogenin (vtg) expression. A rapid and sensitive assessment procedure was established with the 3-day administration of estradiol (E2), followed by examination of the transcriptional expression of vtgs in our cyp17a1-deficient fish. Compared with the control fish, a higher E2-mediated vtg upregulation observed in cyp17a1-deficient zebrafish exposed to 0.1 μg/L E2 is known to be estrogen receptor-dependent and likely due to impaired in vivo estrogen biosynthesis. The more responsive vtg expression in cyp17a1-deficient zebrafish was observed when exposed to 200 and 2000 μg/L bisphenol A (BPA) and perfluoro-1-octanesulfonate (PFOS). The estrogenic potentials of E2, BPA, and PFOS were compared and assessed by the feminization effect on ovarian differentiation in cyp17a1-deficient zebrafish from 18 to 50 days postfertilization, based on which a higher sensitivity of E2 in ovarian differentiation than BPA and PFOS was concluded. Collectively, through the higher sensitivity to EEs and the capacity to distinguish chemicals with different estrogenic potentials exhibited by the all-male cyp17a1-deficient zebrafish with impaired estrogen biosynthesis, we demonstrated that they can be used as an excellent in vivo model for the evaluation of EEs. Environ Toxicol Chem 2024;43:1062-1074. © 2024 SETAC.

PPARγ antagonists induce aromatase transcription in adipose tissue cultures

Aromatase is the rate-limiting enzyme in the biosynthesis of estrogens and a key risk factor for hormone receptor-positive breast cancer. In postmenopausal women, estrogens synthesized in adipose tissue promotes the growth of estrogen receptor positive breast cancers. Activation of peroxisome proliferator-activated receptor gamma (PPARγ) in adipose stromal cells (ASCs) leads to decreased expression of aromatase and differentiation of ASCs into adipocytes. Environmental chemicals can act as antagonists of PPARγ and disrupt its function. This study aimed to test the hypothesis that PPARγ antagonists can promote breast cancer by stimulating aromatase expression in human adipose tissue.Primary cells and explants from human adipose tissue as well as A41hWAT, C3H10T1/2, and H295R cell lines were used to investigate PPARγ antagonist-stimulated effects on adipogenesis, aromatase expression, and estrogen biosynthesis. Selected antagonists inhibited adipocyte differentiation, preventing the adipogenesis-associated downregulation of aromatase. NMR spectroscopy confirmed direct interaction between the potent antagonist DEHPA and PPARγ, inhibiting agonist binding. Short-term exposure of ASCs to PPARγ antagonists upregulated aromatase only in differentiated cells, and a similar effect could be observed in human breast adipose tissue explants. Overexpression of PPARG with or without agonist treatment reduced aromatase expression in ASCs.The data suggest that environmental PPARγ antagonists regulate aromatase expression in adipose tissue through two mechanisms. The first is indirect and involves inhibition of adipogenesis, while the second occurs more acutely.

Interaction of Perfumes with Cytochrome P-450 19

Cytochrome P450 (CYP) enzymes play a key role in the metabolism of foreign compounds and in the biosynthesis and catabolism of endogenous substances, including hormones. The activity of these enzymes can be affected by various xenobiotics, such as pollutants, food constituents, pharmaceuticals, and cosmetic products, which can disrupt the endocrine system by interfering with steroidogenic CYPs. CYP19, also known as aromatase, is a crucial enzyme for testosterone conversion into 17β-estradiol, which is the final step in estrogen biosynthesis. Endocrine disruptors have the potential to inhibit CYP19 activity, leading to an imbalance in estrogen levels in the body. This imbalance can impair reproduction and cause osteoporosis, atherosclerosis, dementia, and some types of cancer. The aim of this study was to assess the effect of commercially available perfumes on testosterone aromatization to 17β-estradiol. For this purpose, we used high-performance liquid chromatography (HPLC) with UV detection and HPLC coupled with mass spectrometry (MS) to examine CYP19 activity with and without perfume. The results showed that all perfumes tested (in a 300-fold dilution) had an inhibitory effect on this enzyme-catalyzed reaction, particularly the Montale® fragrance, ‘Intense Roses Musk’, which decreased 17β-estradiol production by 88% in comparison with the control. Upon exposure to UV light, the inhibitory effect of this perfume did not decrease. But exposure to UV light significantly increased the inhibitory capacity of another perfume with a weak baseline inhibitory effect. To ascertain whether this inhibition was caused by CYP19 interactions with perfumes, we measured the catalytic activity of NADPH:cytochrome P450 oxidoreductase (CYPOR), the CYP reaction partner, with one selected perfume, ‘Intense Roses Musk’ by Montale®, and found no significant CYPOR inhibition. Accordingly, the decrease in testosterone conversion into 17β-estradiol caused by this perfume derives solely from CYP19. Combined, our findings highlight the importance of testing perfumes rather than single ingredients to determine their potential for adverse effects and to ensure consumer safety because their mixtures can interfere with a key enzyme of estrogen biosynthesis.

Molecular Modeling Study of Bis-sulfonamide Derivatives Synthesis Targeting Aromatase Enzyme as Anticancer

Most studies indicate the important role of estrogen in the mechanism of occurrence and development of breast cancer. The importance of our research is the synthesis of bis-sulfonamide compounds that inhibit the aromatase enzyme, which is the main enzyme in the biosynthesis of estrogen. Molecular modeling of studied compounds was carried out by Molegro Virtual Docker (MVD) targeting aromatase enzyme and binding energy calculated to select the most encouraging compound. The highest binding energy among the studied compounds was -118.52 kcal/mol (compound A5) comparing with the aromatase substrate androstenedione -132.51 kcal/mol and the aromatase inhibitor letrozole -136.52 kcal/mol. Several of these compounds were synthesized in a simple way with good yields by reacting sulfonyl chloride derivatives with amino derivatives in an alkaline aqueous solution, or in a pyridine solution. The physicochemical characteristics and identification of synthesized compounds were determined by various analytical methods such as Mass spectrometry, Infrared spectroscopy and Nuclear Magnetic Resonance.

Aromatase inhibition using Juniperus procera phytochemical constituents: molecular docking study

The key step in the biosynthesis of estrogen is the enzyme activity of aromatase. Several malignancies, including breast cancer, have been linked to the initiation and progression of estrogen overexpression. Exemestane, Arimidex and Femara are the most common aromatase inhibitors used to treat hormone-dependent breast cancers. Drug resistance and side effects are commonly associated with these treatments. The purpose of this in silico study was to list the chemical compounds of Juniperus procera that have been published in scientific papers. The second goal was to evaluate the inhibitory activity of 124 phytochemicals of Juniperus procera compared to known aromatase inhibitors such as Exemestane, Arimidex and Femara. The 3D structure of aromatase (PDB id: 3s7s) employed for docking studies using AutoDock Tools as well as normal mode analysis studies utilizing the NMSim web server. Juniperolide, Kaurenoic acid and Isocupressic acid were identified as competitive aromatase inhibitors compared to FDA approved anti-cancer drugs, specifically Exemestane, Arimidex and Femara. The stability of the ligand–protein interface was studied to support the docking findings. To our knowledge, this is the first study that investigates the possible inhibition roles of some compounds of Juniperus procera on the aromatase enzyme.