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European Journal of Drug Metabolism and... Jan 2021Previous studies have revealed that sulfation, as mediated by the estrogen-sulfating cytosolic sulfotransferase (SULT) SULT1E1, is involved in the metabolism of...
BACKGROUND AND OBJECTIVES
Previous studies have revealed that sulfation, as mediated by the estrogen-sulfating cytosolic sulfotransferase (SULT) SULT1E1, is involved in the metabolism of 17β-estradiol (E2), 4-hydroxytamoxifen (4OH-tamoxifen), and diethylstilbestrol in humans. It is an interesting question whether the genetic polymorphisms of SULT1E1, the gene that encodes the SULT1E1 enzyme, may impact on the metabolism of E2 and these two drug compounds through sulfation.
METHODS
In this study, five missense coding single nucleotide polymorphisms of the SULT1E1 gene were selected to investigate the sulfating activity of the coded SULT1E1 allozymes toward E2, 4OH-tamoxifen, and diethylstilbestrol. Corresponding cDNAs were generated by site-directed mutagenesis, and recombinant SULT1E1 allozymes were bacterially expressed, affinity-purified, and characterized using enzymatic assays.
RESULTS
Purified SULT1E1 allozymes were shown to display differential sulfating activities toward E2, 4OH-tamoxifen, and diethylstilbestrol. Kinetic analysis revealed further distinct K (reflecting substrate affinity) and V (reflecting catalytic activity) values of the five SULT1E1 allozymes with E2, 4OH-tamoxifen, and diethylstilbestrol as substrates.
CONCLUSIONS
Taken together, these findings highlighted the significant differences in E2-, as well as the drug-sulfating activities of SULT1E1 allozymes, which may have implications in the differential metabolism of E2, 4OH-tamoxifen, and diethylstilbestrol in individuals with different SULT1E1 genotypes.
Topics: Diethylstilbestrol; Dose-Response Relationship, Drug; Estradiol; Estrogen Antagonists; Estrogens; Estrogens, Non-Steroidal; Humans; Isoenzymes; Polymorphism, Single Nucleotide; Protein Structure, Secondary; Sulfotransferases; Tamoxifen
PubMed: 33064293
DOI: 10.1007/s13318-020-00653-1 -
International Journal of Molecular... Sep 2022Cyclic nucleotides (cAMP, cGMP) play a major role in normal and pathologic signaling. Beyond receptors, cyclic nucleotide phosphodiesterases; (PDEs) rapidly convert the... (Review)
Review
Cyclic nucleotides (cAMP, cGMP) play a major role in normal and pathologic signaling. Beyond receptors, cyclic nucleotide phosphodiesterases; (PDEs) rapidly convert the cyclic nucleotide in its respective 5'-nucleotide to control intracellular cAMP and/or cGMP levels to maintain a normal physiological state. However, in many pathologies, dysregulations of various PDEs (PDE1-PDE11) contribute mainly to organs and tissue failures related to uncontrolled phosphorylation cascade. Among these, PDE4 represents the greatest family, since it is constituted by 4 genes with multiple variants differently distributed at tissue, cellular and subcellular levels, allowing different fine-tuned regulations. Since the 1980s, pharmaceutical companies have developed PDE4 inhibitors (PDE4-I) to overcome cardiovascular diseases. Since, they have encountered many undesired problems, (emesis), they focused their research on other PDEs. Today, increases in the knowledge of complex PDE4 regulations in various tissues and pathologies, and the evolution in drug design, resulted in a renewal of PDE4-I development. The present review describes the recent PDE4-I development targeting cardiovascular diseases, obesity, diabetes, ulcerative colitis, and Crohn's disease, malignancies, fatty liver disease, osteoporosis, depression, as well as COVID-19. Today, the direct therapeutic approach of PDE4 is extended by developing allosteric inhibitors and protein/protein interactions allowing to act on the PDE interactome.
Topics: 3',5'-Cyclic-AMP Phosphodiesterases; COVID-19; Cardiovascular Diseases; Cyclic GMP; Cyclic Nucleotide Phosphodiesterases, Type 4; Diethylstilbestrol; Humans; Nucleotides, Cyclic; Pharmaceutical Preparations; Phosphodiesterase 4 Inhibitors; Phosphoric Diester Hydrolases
PubMed: 36142518
DOI: 10.3390/ijms231810616 -
Trends in Endocrinology and Metabolism:... Sep 2009Growing concerns over endocrine disrupting chemicals (EDCs) and their effects on human fetal development and adult health have promoted research into the underlying... (Review)
Review
Growing concerns over endocrine disrupting chemicals (EDCs) and their effects on human fetal development and adult health have promoted research into the underlying molecular mechanisms of endocrine disruption. Gene targeting technology has allowed insight into the genetic pathways governing reproductive tract development and how exposure to EDCs during a critical developmental window can alter reproductive tract development, potentially forming the basis for adult diseases. This review primarily uses diethylstilbestrol (DES) as a model agent for EDCs and discusses the recent progress elucidating how DES and other EDCs affect murine female reproductive tract development and cancer at the molecular level.
Topics: Animals; Diethylstilbestrol; Endocrine Disruptors; Female; Genitalia, Female; Humans; Mice; Mullerian Ducts; Pregnancy; Prenatal Exposure Delayed Effects
PubMed: 19709900
DOI: 10.1016/j.tem.2009.03.009 -
Archives of Sexual Behavior Feb 2020We assessed the associations of prenatal diethylstilbestrol (DES) exposure, a potent estrogen, with sexual orientation and gender identity in 3306 women and 1848 men who...
We assessed the associations of prenatal diethylstilbestrol (DES) exposure, a potent estrogen, with sexual orientation and gender identity in 3306 women and 1848 men who participated in a study of prenatal DES exposure. Odds ratios (OR) and 95% confidence intervals (CI) were derived from logistic regression models adjusted for birth year, study cohort, and education. Among women, the OR for DES in relation to reporting sexual orientation identity as nonheterosexual was 0.61 (95% CI 0.40-0.92) primarily due to a strong inverse association with a lesbian identity (OR 0.44, 95% CI 0.25-0.76). Among men, the OR for DES in relation to reporting a nonheterosexual sexual orientation identity was 1.4 (95% CI 0.82-2.4), and ORs were similar for having a gay identity (1.4, 95% CI 0.72-2.85) and bisexual identity (1.4, 95% CI 0.57-3.5). Only five individuals reported a gender identity not conforming to that assigned at birth, preventing meaningful analysis. Women who were prenatally exposed to DES were less likely to have a lesbian or bisexual orientation, while DES-exposed men were somewhat more likely to report being gay or bisexual, but estimates were imprecise.
Topics: Cohort Studies; Diethylstilbestrol; Female; Gender Identity; Humans; Longitudinal Studies; Male; Middle Aged; Pregnancy; Prenatal Exposure Delayed Effects; Sexual Behavior
PubMed: 31975033
DOI: 10.1007/s10508-020-01637-7 -
Canadian Medical Association Journal Jun 1979
Topics: Abnormalities, Drug-Induced; Breast Neoplasms; Diethylstilbestrol; Female; Fetus; Humans; Male; Neoplasms; Pregnancy; Pregnancy Complications; Risk; Uterine Cervical Neoplasms; Vaginal Neoplasms
PubMed: 455196
DOI: No ID Found -
Biomedical and Environmental Sciences :... Apr 2013To study whether effect of aspirin plus low-dose diethylstilbestrol is more effective and safer than high diethylstilbestrol dose alone on prevention of...
OBJECTIVE
To study whether effect of aspirin plus low-dose diethylstilbestrol is more effective and safer than high diethylstilbestrol dose alone on prevention of ovariectomy-induced osteopenia and dyslipidemia.
METHODS
Thirty-eight 4-month-old female SD rats were divided into baseline (BAS) group (n=6), sham operation group (n=8) and ovariectomy (OVX) group (n=24). The OVX group was further divided into vehicle treatment group (n=8), diethylstilbestrol (30 μg/kg•d) treatment group (OVX+D30 group, n=8), and aspirin (9 mg/kg•d) plus diethylstilbestrol (10 μg/kg•d) treatment group (OVX+A-D10 group, n=8). Their left tibiae were collected for the bone histomorphometric analysis in undecalcified sections. Left femurs were collected for the bone mineral density measurement.
RESULTS
The body weight and serum cholesterol were increased, while uterine weight and cancellous bone mass were decreased in OVX rats compared with the SHAM group. Cancellous bone mass was significantly increased, while body weight and bone resorption parameters were decreased in both A-D10 and D30 treatment group compared with OVX group. The rats treated with A-D10 showed significantly increased in bone formation parameters and decreased in serum triglyceride compared with the D30-treated rats.
CONCLUSION
Aspirin plus low-dose diethylstilbestrol can effectively prevent osteopenia by reducing bone resorption, and is thus a better treatment modality for preventing dyslipidemia than high-dose diethylstilbestrol alone.
Topics: Animals; Anti-Inflammatory Agents, Non-Steroidal; Aspirin; Biomarkers; Body Weight; Bone Density; Bone Diseases, Metabolic; Bone and Bones; Diethylstilbestrol; Drug Evaluation, Preclinical; Drug Therapy, Combination; Dyslipidemias; Estrogens, Non-Steroidal; Female; Organ Size; Ovariectomy; Rats; Uterus
PubMed: 23534465
DOI: 10.3967/0895-3988.2013.04.003 -
Breast Cancer Research : BCR 2002High-dose estrogen was generally considered the endocrine therapy of choice for postmenopausal women with breast cancer prior to the introduction of tamoxifen.... (Comparative Study)
Comparative Study
High-dose estrogen was generally considered the endocrine therapy of choice for postmenopausal women with breast cancer prior to the introduction of tamoxifen. Subsequently, the use of estrogen was largely abandoned. Recent clinical trial data have shown clinically meaningful efficacy for high-dose estrogen even in patients with extensive prior endocrine therapy. Preclinical research has demonstrated that the estrogen dose-response curve for breast cancer cells can be shifted by modification of the estrogen environment. Clinical and laboratory data together provide the basis for developing testable hypotheses of management strategies, with the potential of increasing the value of endocrine therapy in women with breast cancer.
Topics: Anastrozole; Androstadienes; Antineoplastic Agents, Hormonal; Breast Neoplasms; Clinical Trials, Phase II as Topic; Diethylstilbestrol; Dose-Response Relationship, Drug; Drug Resistance, Neoplasm; Estrogens; Female; Humans; Letrozole; Megestrol Acetate; Middle Aged; Neoplasms, Hormone-Dependent; Nitriles; Postmenopause; Salvage Therapy; Tamoxifen; Treatment Outcome; Triazoles
PubMed: 12100736
DOI: 10.1186/bcr436 -
JAMA Pediatrics Jul 2018
Toward an Emerging Paradigm for Understanding Attention-Deficit/Hyperactivity Disorder and Other Neurodevelopmental, Mental, and Behavioral Disorders: Environmental Risks and Epigenetic Associations.
Topics: Attention Deficit Disorder with Hyperactivity; Diethylstilbestrol; Epigenesis, Genetic; Epigenomics; Female; Humans; Pregnancy
PubMed: 29799950
DOI: 10.1001/jamapediatrics.2018.0920 -
British Medical Journal Nov 1968
Topics: Breast Feeding; Diethylstilbestrol; Female; Humans; Lactation; Pregnancy; Puerperal Disorders; Thromboembolism
PubMed: 5687615
DOI: 10.1136/bmj.4.5628.451-a -
Proceedings of the National Academy of... Jan 2024Phosphodiesterases (PDEs) encoded by viruses are putatively acquired by horizontal transfer of cellular PDE ancestor genes. Viral PDEs inhibit the OAS-RNase L antiviral...
Phosphodiesterases (PDEs) encoded by viruses are putatively acquired by horizontal transfer of cellular PDE ancestor genes. Viral PDEs inhibit the OAS-RNase L antiviral pathway, a key effector component of the innate immune response. Although the function of these proteins is well-characterized, the origins of these gene acquisitions are less clear. Phylogenetic analysis revealed at least five independent PDE acquisition events by ancestral viruses. We found evidence that PDE-encoding genes were horizontally transferred between coronaviruses belonging to different genera. Three clades of viruses within : merbecoviruses (MERS-CoV), embecoviruses (HCoV-OC43), and toroviruses encode independently acquired PDEs, and a clade of rodent alphacoronaviruses acquired an embecovirus PDE via recent horizontal transfer. Among rotaviruses, the PDE of rotavirus A was acquired independently from rotavirus B and G PDEs, which share a common ancestor. Conserved motif analysis suggests a link between all viral PDEs and a similar ancestor among the mammalian AKAP7 proteins despite low levels of sequence conservation. Additionally, we used ancestral sequence reconstruction and structural modeling to reveal that sequence and structural divergence are not well-correlated among these proteins. Specifically, merbecovirus PDEs are as structurally divergent from the ancestral protein and the solved structure of human AKAP7 PDE as they are from each other. In contrast, comparisons of rotavirus B and G PDEs reveal virtually unchanged structures despite evidence for loss of function in one, suggesting impactful changes that lie outside conserved catalytic sites. These findings highlight the complex and volatile evolutionary history of viral PDEs and provide a framework to facilitate future studies.
Topics: Animals; Humans; Phosphoric Diester Hydrolases; Phylogeny; Middle East Respiratory Syndrome Coronavirus; Mammals; Diethylstilbestrol; Endoribonucleases; Rotavirus
PubMed: 38277437
DOI: 10.1073/pnas.2312691121