Steroids with a nitrogen-containing heterocycle in the side chain are known as effective inhibitors of androgen signaling and/or testosterone biosynthesis, thus showing beneficial effects for the treatment of prostate cancer. In this work, a series of 3β-hydroxy-5-ene steroids, containing an isoxazole fragment in their side chain, was synthesized. The key steps included the preparation of Weinreb amide, its conversion to acetylenic ketones, and the 1,2- or 1,4-addition of hydroxylamine, depending on the solvent used. The biological activity of the obtained compounds was studied in a number of tests, including their effects on 17α-hydroxylase and 17,20-lyase activity of human CYP17A1 and the ability of selected compounds to affect the downstream androgen receptor signaling. Three derivatives diminished the transcriptional activity of androgen receptor and displayed reasonable antiproliferative activity. The candidate compound, 24j (17R)-17-((3-(2-hydroxypropan-2-yl)isoxazol-5-yl)methyl)-androst-5-en-3β-ol, suppressed the androgen receptor signaling and decreased its protein level in two prostate cancer cell lines, LNCaP and LAPC-4. Interaction of compounds with CYP17A1 and the androgen receptor was confirmed and described by molecular docking.
- Klíčová slova
- CYP17A1, LAPC-4, LNCaP, Weinreb amide, androgen receptor, androgen signaling, isoxazoles, molecular docking, prostate cancer,
- MeSH
- androgenní receptory metabolismus MeSH
- antitumorózní látky * chemie MeSH
- lidé MeSH
- nádorové buněčné linie MeSH
- nádory prostaty * farmakoterapie metabolismus MeSH
- simulace molekulového dockingu MeSH
- steroid-17-alfa-hydroxylasa metabolismus MeSH
- steroidy farmakologie terapeutické užití MeSH
- Check Tag
- lidé MeSH
- mužské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
- Názvy látek
- androgenní receptory MeSH
- antitumorózní látky * MeSH
- steroid-17-alfa-hydroxylasa MeSH
- steroidy MeSH
Gestational diabetes mellitus (GDM) is a complication in pregnancy, but studies focused on the steroidome in patients with GDM are not available in the public domain. This article evaluates the steroidome in GDM+ and GDM- women and its changes from 24 weeks (± of gestation) to labor. The study included GDM+ (n = 44) and GDM- women (n = 33), in weeks 24-28, 30-36 of gestation and at labor and mixed umbilical blood after delivery. Steroidomic data (101 steroids quantified by GC-MS/MS) support the concept that the increasing diabetogenic effects with the approaching term are associated with mounting progesterone levels. The GDM+ group showed lower levels of testosterone (due to reduced AKR1C3 activity), estradiol (due to a shift from the HSD17B1 towards HSD17B2 activity), 7-oxygenated androgens (competing with cortisone for HSD11B1 and shifting the balance from diabetogenic cortisol towards the inactive cortisone), reduced activities of SRD5As, and CYP17A1 in the hydroxylase but higher CYP17A1 activity in the lyase step. With the approaching term, the authors found rising activities of CYP3A7, AKR1C1, CYP17A1 in its hydroxylase step, but a decline in its lyase step, rising conjugation of neuroinhibitory and pregnancy-stabilizing steroids and weakening AKR1D1 activity.
- Klíčová slova
- gas chromatography-tandem mass spectrometry, gestational age, gestational diabetes mellitus, immunoprotective steroids, maternal blood, mixed cord blood, neuroactive steroids, steroidome,
- MeSH
- 20-hydroxysteroid dehydrogenasy metabolismus MeSH
- chromatografie plynová MeSH
- cytochrom P-450 CYP3A metabolismus MeSH
- druhý trimestr těhotenství metabolismus MeSH
- gestační diabetes metabolismus MeSH
- lidé MeSH
- metabolomika metody MeSH
- oxidoreduktasy metabolismus MeSH
- steroid-17-alfa-hydroxylasa metabolismus MeSH
- steroidy analýza MeSH
- tandemová hmotnostní spektrometrie MeSH
- těhotenství MeSH
- Check Tag
- lidé MeSH
- těhotenství MeSH
- ženské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- Názvy látek
- 20-hydroxysteroid dehydrogenasy MeSH
- 3 alpha-beta, 20 beta-hydroxysteroid dehydrogenase MeSH Prohlížeč
- 3-oxo-5 beta-steroid delta 4-dehydrogenase MeSH Prohlížeč
- CYP17A1 protein, human MeSH Prohlížeč
- CYP3A7 protein, human MeSH Prohlížeč
- cytochrom P-450 CYP3A MeSH
- oxidoreduktasy MeSH
- steroid-17-alfa-hydroxylasa MeSH
- steroidy MeSH
BACKGROUND: Epilepsy in women may be associated with reproductive disorders and alterations in serum steroid levels. Some steroids can be induced by epilepsy and/or treatment with antiepileptic drugs; however, there are still limited data available concerning this effect on the levels of other neuroactive steroid metabolites such as 3a-hydroxy-5a/b-reduced androstanes. AIM: To evaluate steroid alterations in women with epilepsy (WWE) on lamotrigine monotherapy. SUBJECTS AND METHODS: Eleven WWE and 11 age-matched healthy women underwent blood sampling in both phases of their menstrual cycles (MCs). The steroid metabolome, which included 30 unconjugated steroids, 17 steroid polar conjugates, gonadotropins, and sex hormone-binding globulin (SHBG), was measured using gas chromatography-mass spectrometry (GC-MS) and radioimmunoassay (RIA). RESULTS: WWE had lower cortisol levels (status p<0.001), but elevated levels of unconjugated 17-hydroxypregnenolone (status p<0.001). Progesterone was higher in the follicular menstrual phase (FP) in WWE than in the controls (status×menstrual phase p<0.05, Bonferroni multiple comparisons p<0.05), whereas 17-hydroxyprogesterone was higher in WWE in both menstrual phases (status p<0.001). The steroid conjugates were mostly elevated in WWE. The levels of 5α/β-reduced androstanes in WWE that were significantly higher than the controls were etiocholanolone (status p<0.001), 5α-androstane-3α,17β-diol (status p<0.001), and the 5α/β-reduced androstane polar conjugates (status p<0.001). CONCLUSIONS: WWE showed a trend toward higher circulating 3α-hydroxy-5α/β-reduced androstanes, increased activity of 17α-hydroxylase/17,20 lyase in the Δ(5)-steroid metabolic pathway, and increased levels of the steroid polar conjugates.
- MeSH
- 17-alfa-hydroxypregnenolon krev MeSH
- androstanoly krev MeSH
- androstany krev metabolismus MeSH
- antikonvulziva škodlivé účinky terapeutické užití MeSH
- dospělí MeSH
- epilepsie farmakoterapie metabolismus MeSH
- lamotrigin MeSH
- lidé MeSH
- metabolom MeSH
- steroid-17-alfa-hydroxylasa krev MeSH
- triaziny škodlivé účinky terapeutické užití MeSH
- Check Tag
- dospělí MeSH
- lidé MeSH
- ženské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- Názvy látek
- 17-alfa-hydroxypregnenolon MeSH
- androstanoly MeSH
- androstany MeSH
- antikonvulziva MeSH
- lamotrigin MeSH
- steroid-17-alfa-hydroxylasa MeSH
- triaziny MeSH
Gender differences in CAD have been clearly documented, and sex hormones have been recognized to influence the risk of CAD. The cytochrome P450c17alpha gene (CYP17) and the CYP19 gene influence concentrations of sex hormones. In this cross-sectional association study we tested the hypothesis whether the T/C polymorphism of the CYP17 gene and the tetranucleotide repeat (TTTA) polymorphism of the CYP19 gene are genetic markers for CAD in Caucasians. The TT genotype of the CYP17 gene polymorphism was not associated with premature CAD in men and women combined (OR 0.9; 95% CI = 0.6-1.4; P = 0.7), in men only (OR 1; 95% CI = 0.6-1.8; P = 0.7), and in women only (OR 0.8; 95% CI = 0.5-1.4; P = 0.4). The tetranucleotide repeat (TTTA) CYP19 gene polymorphism was not associated with premature CAD. Moreover, the genotypes containing the longer alleles (A6 or A7) were not associated with a lower incidence of CAD, and the genotypes containing the shorter alleles (A1 or A2) were not over-represented in the CAD patients. We may conclude that in Caucasian subjects neither the T/C CYP17 gene polymorphism nor the tetranucleotide repeat (TTTA) polymorphism of the CYP19 gene contributes to the genetic susceptibility to CAD, therefore they may not be used as genetic markers for CAD risk assessment.
- MeSH
- alely MeSH
- aromatasa genetika MeSH
- běloši genetika MeSH
- genetické markery genetika MeSH
- genotyp MeSH
- lidé středního věku MeSH
- lidé MeSH
- mikrosatelitní repetice genetika MeSH
- nemoci koronárních tepen etnologie genetika MeSH
- polymorfismus genetický * MeSH
- steroid-17-alfa-hydroxylasa genetika MeSH
- studie případů a kontrol MeSH
- věk při počátku nemoci MeSH
- Check Tag
- lidé středního věku MeSH
- lidé MeSH
- mužské pohlaví MeSH
- ženské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
- Názvy látek
- aromatasa MeSH
- genetické markery MeSH
- steroid-17-alfa-hydroxylasa MeSH
Polycystic ovary syndrome (PCOS) is connected with insulin resistance (IR), and often with the hypersecretion of adrenal androgens. Mutual relationships between IR and adrenal and ovarian steroidogenesis were investigated in the group of 19 oligo/amenorhoeic women with PCOS. The age and body mass index (BMI) of the patients were 21+/-4.7 years and 26.4+/-5 kg/m2 (average+/-SD), respectively. All underwent a 60-minute adrenocorticotrophic hormone (ACTH) stimulation test, a gonadoliberin analogue (GnRHa) test with buserelin and an oral glucose tolerance test (oGTT) in the early follicular phase of the menstrual cycle. When absolute stimulated steroid levels after GnRHa were studied, a significant positive correlation between DHEA and area under curve during oGTT for C peptide (AUC-CP) (r=0.477, p= 0.039) and a borderline negative correlation (r=-0.404, p= 0.087) between AUC-CP and 17-OH progesterone, were found. Considering steroid values after ACTH, a significant positive correlation of IR index was found only with 17-OH-progesterone (r=0.499, p= 0.03). When stimulated enzymatic activities (expressed as product/ precursor ratios) were analyzed using factor analysis, a positive relationship between IR and ovarian C17,20-lyase in both delta4 and delta5 pathway was revealed. On the other hand, no relationship was confirmed between IR and enzymatic activities in the adrenals. The authors conclude that insulin resistance and/or hyperinsulinemia is probably not the primary factor responsible for the exaggerated adrenal androgen secretion found in a great number of patients with PCOS.
- MeSH
- 17-alfa-hydroxyprogesteron krev MeSH
- 3-hydroxysteroid dehydrogenasy metabolismus MeSH
- adrenokortikotropní hormon MeSH
- androgeny krev MeSH
- C-peptid krev MeSH
- dehydroepiandrosteron krev MeSH
- dospělí MeSH
- faktorová analýza statistická MeSH
- glukózový toleranční test MeSH
- hydrokortison krev MeSH
- inzulinová rezistence * MeSH
- krevní glukóza metabolismus MeSH
- lidé MeSH
- nadledviny enzymologie MeSH
- ovarium enzymologie MeSH
- referenční hodnoty MeSH
- steroid-17-alfa-hydroxylasa metabolismus MeSH
- syndrom polycystických ovarií krev enzymologie patofyziologie MeSH
- Check Tag
- dospělí MeSH
- lidé MeSH
- ženské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- Názvy látek
- 17-alfa-hydroxyprogesteron MeSH
- 3-hydroxysteroid dehydrogenasy MeSH
- adrenokortikotropní hormon MeSH
- androgeny MeSH
- C-peptid MeSH
- dehydroepiandrosteron MeSH
- hydrokortison MeSH
- krevní glukóza MeSH
- steroid-17-alfa-hydroxylasa MeSH
Epitestosterone (17 alpha-hydroxy-4-androsten-3-one) inhibited competitively 17 alpha-hydroxylation of pregnenolone and subsequent C17,20-side chain cleavage of resulting 17 alpha-hydroxypregnenolone using microsomal preparations from the human testis. The inhibition constants for 17 alpha-hydroxylase and C17,20-lyase with 5-ene-precursors of C21-steroids were 96 and 12.4 mumol/l, respectively.
- MeSH
- aldehydlyasy antagonisté a inhibitory MeSH
- epitestosteron farmakologie MeSH
- inhibitory cytochromu P450 * MeSH
- kinetika MeSH
- lidé MeSH
- steroid-17-alfa-hydroxylasa antagonisté a inhibitory MeSH
- testis enzymologie MeSH
- Check Tag
- lidé MeSH
- mužské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- Názvy látek
- aldehydlyasy MeSH
- epitestosteron MeSH
- inhibitory cytochromu P450 * MeSH
- steroid-17-alfa-hydroxylasa MeSH
