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Journal of Lipid Research Feb 2013Cellular cholesterol is known to be under homeostatic control in nonsteroidogenic cells, and this intrigued us to understand how such control works in steroidogenic...
Cellular cholesterol is known to be under homeostatic control in nonsteroidogenic cells, and this intrigued us to understand how such control works in steroidogenic cells that additionally use cholesterol for steroid hormone synthesis. We employed primary culture of rat ovarian granulosa cells to study how steroidogenic cells adapt to acquire sufficient cholesterol to meet the demand of active steroidogenesis under the stimulation of gonadotropin follicle-stimulating hormone (FSH) and cytokine transforming growth factor (TGF)β1. We found that TGFβ1 potentiated FSH to upregulate scavenger receptor class B member I (SR-BI) and LDL receptor (LDLR), both functional in uptaking cholesterol as hHDL(3) and hLDL supplementation enhanced progesterone production, and the effect of each lipoprotein was completely or partially blocked by SR-BI selective inhibitor BLT-1. Uptaken cholesterol could also be stored in lipid droplets. Importantly, LDLR and SR-BI responded to sterol with different sensitivity. Giving cells lipoproteins or 25-hydroxycholesterol downregulated Ldlr but not Scarb1; Scarb1 was ultimately downregulated by excessive sterol accumulation under 25-hydroxycholesterol and aminoglutethimide (inhibitor of steroidogenesis) cotreatment. Furthermore, transcription factors sterol regulatory element-binding protein (SREBP)-2 and liver receptor homolog (LRH)-1 crucially mediated Ldlr and Scarb1 differential response to sterol challenge. This study reveals that ovarian granulosa cells retain the cholesterol homeostatic control machinery like nonsteroidogenic cells, although during active steroidogenesis, they utilize SR-BI to evade such feedback control.
Topics: Animals; CD36 Antigens; Cholesterol; Female; Follicle Stimulating Hormone; Gene Expression Regulation; Granulosa Cells; Homeostasis; Humans; Intracellular Space; Protein Transport; Rats; Rats, Sprague-Dawley; Receptors, Cytoplasmic and Nuclear; Receptors, LDL; Steroids; Sterol Regulatory Element Binding Protein 2; Transforming Growth Factor beta1
PubMed: 23197320
DOI: 10.1194/jlr.M030239 -
Annals of Oncology : Official Journal... Jun 1998The study compares letrozole and aminoglutethimide (AG), a standard therapy for postmenopausal women with advanced breast cancer, previously treated with antioestrogens. (Clinical Trial)
Clinical Trial Comparative Study Randomized Controlled Trial
Letrozole, a new oral aromatase inhibitor: randomised trial comparing 2.5 mg daily, 0.5 mg daily and aminoglutethimide in postmenopausal women with advanced breast cancer. Letrozole International Trial Group (AR/BC3).
BACKGROUND
The study compares letrozole and aminoglutethimide (AG), a standard therapy for postmenopausal women with advanced breast cancer, previously treated with antioestrogens.
PATIENTS AND METHODS
555 women were randomly assigned letrozole 2.5 mg once daily (n = 185), letrozole 0.5 mg once daily (n = 192) or aminoglutethimide 250 mg twice daily with corticosteroid support (n = 178) in an open-label, multicentre trial. The primary endpoint was objective response rate (ORR), with time events as secondary. ORR was analysed nine months after enrollment of the last patient, while survival was analysed 15 months after the last patient was enrolled. We report the results of these analyses plus an extended period of observation (covering a total duration of approximately 45 months) to determine the duration of response and clinical benefit.
RESULTS
Overall objective response rates (complete + partial) of 19.5%, 16.7% and 12.4% were seen for letrozole 2.5 mg, 0.5 mg and AG respectively. Median duration of response and stable disease was longest for letrozole 2.5 mg (21 months) compared with letrozole 0.5 mg (18 months) and AG (14 months). Letrozole 2.5 mg was superior to AG in time to progression, time to treatment failure and overall survival. Treatment-related adverse events occurred in fewer patients on letrozole (33%) than on AG (46%). Transient nausea was the most frequent event with letrozole (7% on 0.5 mg, 10% on 2.5 mg, 10% on AG), rash with AG (11%, 1% on 0.5 mg, 3% on 2.5 mg letrozole).
CONCLUSIONS
Letrozole 2.5 mg offers longer disease control than aminoglutethimide and letrozole 0.5 mg in the treatment of postmenopausal women with advanced breast cancer, previously treated with anti-oestrogens.
Topics: Administration, Oral; Aged; Aminoglutethimide; Antineoplastic Agents, Hormonal; Breast Neoplasms; Confidence Intervals; Disease Progression; Dose-Response Relationship, Drug; Enzyme Inhibitors; Female; Humans; Letrozole; Middle Aged; Neoplasm Staging; Nitriles; Odds Ratio; Postmenopause; Prognosis; Survival Rate; Treatment Failure; Triazoles
PubMed: 9681078
DOI: 10.1023/a:1008226721932 -
British Journal of Cancer Jul 1982Gonadotrophins, oestradiol, androstenedione, testosterone and dehydroepiandrosterone sulphate (DHAS) were measured sequentially in 72 patients with advanced breast...
Gonadotrophins, oestradiol, androstenedione, testosterone and dehydroepiandrosterone sulphate (DHAS) were measured sequentially in 72 patients with advanced breast cancer receiving endocrine therapy of various types. Tamoxifen significantly reduced gonadotrophins but did not effect other hormones. Danazol also reduced gonadotrophins. Aminoglutethimide (AGT) reduced oestradiol and DHAS but had not effect on gonadotrophins. The effects of administering tamoxifen, AGT and danazol together (TAD) together were therefore examined. This combination reduced gonadotrophins, oestradiol and DHAS, but no further than tamoxifen and AGT alone. The degree and duration of hormone suppression were similar in both responders and non-responders to tamoxifen, AGT or TAD, though patients responding to AGT showed more complete suppression at the end of the course of treatment, perhaps because they were treated longer. On relapse, adequate gonadotrophin and steroid suppression was demonstrated in patients receiving tamoxifen and AGT respectively. We conclude that (a) response to endocrine therapy is unlikely to be related to the degree of endocrine suppression produced by the therapy; (b) combination endocrine therapy does not further reduce serum-hormone concentrations and (c) relapse is unlikely to be due to escape from the hormone-inhibitory effects of endocrine agents.
Topics: Aminoglutethimide; Androgens; Antineoplastic Combined Chemotherapy Protocols; Breast Neoplasms; Danazol; Drug Therapy, Combination; Estradiol; Female; Gonadotropins, Pituitary; Hormones; Humans; Menopause; Pregnadienes; Tamoxifen
PubMed: 7104195
DOI: 10.1038/bjc.1982.161 -
Anesthesiology Sep 2017Liver X receptors, including α and β isoforms, are ligand-activated transcription factors. Whether liver X receptor α plays a role in neuropathic pain is unknown.
BACKGROUND
Liver X receptors, including α and β isoforms, are ligand-activated transcription factors. Whether liver X receptor α plays a role in neuropathic pain is unknown.
METHODS
A spared nerve injury model was established in adult male rats and mice. Von Frey tests were performed to evaluate the neuropathic pain behavior; Western blot and immunohistochemistry were performed to understand the underlying mechanisms.
RESULTS
Intrathecal injection of a specific liver X receptor agonist T0901317 or GW3965 could either prevent the development of mechanical allodynia or alleviate the established mechanical allodynia, both in rats and wild-type mice. GW3965 could inhibit the activation of glial cells and the expression of tumor necrosis factor-α (mean ± SD: 196 ± 48 vs. 119 ± 57; n = 6; P < 0.01) and interleukin 1β (mean ± SD: 215 ± 69 vs. 158 ± 74; n = 6; P < 0.01) and increase the expression of interleukin 10 in the spinal dorsal horn. All of the above effects of GW3965 could be abolished by liver X receptor α mutation. Moreover, more glial cells were activated, and more interleukin 1β was released in the spinal dorsal horn in liver X receptor α knockout mice than in wild-type mice after spared nerve injury. Aminoglutethimide, a neurosteroid synthesis inhibitor, blocked the inhibitory effect of T0901317 on mechanical allodynia, on the activation of glial cells, and on the expression of cytokines.
CONCLUSIONS
Activation of liver X receptor α inhibits mechanical allodynia by inhibiting the activation of glial cells and rebalancing cytokines in the spinal dorsal horn via neurosteroids.
Topics: Animals; Blotting, Western; Cytokines; Disease Models, Animal; Hyperalgesia; Immunohistochemistry; Inflammation; Interleukin-1beta; Liver X Receptors; Male; Mice; Mice, Knockout; Neuralgia; Neuroglia; Rats; Rats, Sprague-Dawley; Spinal Cord Dorsal Horn
PubMed: 28617705
DOI: 10.1097/ALN.0000000000001718 -
Journal of Lipid Research Jan 1983This study examined the effects of various drugs and sterols on the rate of 7alpha-hydroxycholesterol synthesis in isolated rat liver microsomes. Cholesterol...
This study examined the effects of various drugs and sterols on the rate of 7alpha-hydroxycholesterol synthesis in isolated rat liver microsomes. Cholesterol 7alpha-hydroxylase activity was significantly inhibited by proadifen (98%), metyrapone (67%), and aminoglutethimide (45%) at concentrations of 1 mM and by ascorbic acid (40%) at a concentration of 10 mM. Cimetidine had no significant effect. The activity of cholesterol 7alpha-hydroxylase was also significantly inhibited by 7beta-hydroxycholesterol (38%) and 7-ketocholesterol (35%) at concentrations of 1 micro M, and by 10 micro M 7alpha-hydroxycholesterol (35%), 25alpha-hydroxycholesterol (32%), and 5-cholenic acid-3beta-ol (27%). Two bile acids, cholate and lithocholate, as well as a geometric isomer of cholesterol, coprostanol, had little influence on 7alpha-hydroxylase activity at concentrations of 10 micro M. The inhibitory effect of metyrapone was additive with that of either 7beta-hydroxycholesterol or proadifen; the effects of 7beta-hydroxycholesterol and proadifen were not additive. These results suggest that proadifen and 7beta-hydroxycholesterol interact with the same enzyme site while metyrapone binds at a different location. Proadifen inhibited 7alpha-hydroxylase irreversibly, while kinetic studies demonstrated noncompetitive inhibition by metyrapone (K(I) = 0.55 mM) and competitive inhibition by 7beta-hydroxycholesterol (K(I) = 2.4 micro M). The inhibition of 7alpha-hydroxylase activity by metyrapone and aminoglutethimide, drugs used to manage patients with excessive cortisol production, suggests that such treatment may also alter bile acid synthesis.-Schwartz, M. A., and S. Margolis. Effects of drugs and sterols on cholesterol 7alpha-hydroxylase activity in rat liver microsomes.
Topics: Aminoglutethimide; Animals; Ascorbic Acid; Bile Acids and Salts; Cholesterol 7-alpha-Hydroxylase; Cimetidine; Kinetics; Male; Metyrapone; Microsomes, Liver; Proadifen; Rats; Rats, Inbred Strains; Steroid Hydroxylases; Sterols
PubMed: 6833879
DOI: No ID Found -
Annals of Surgery May 1978The use of adrenalectomy and hypophysectomy in the management of postmenopausal patients with metastatic breast carcinoma is reserved for highly selected patients. As an...
The use of adrenalectomy and hypophysectomy in the management of postmenopausal patients with metastatic breast carcinoma is reserved for highly selected patients. As an alternate approach, a pharmacologic method of inhibiting adrenal cortical secretion was developed which consisted of the daily administration of 1000 mg of aminoglutethimide to block steroidogensis and either dexamethasone (2.0-3.0 mg/day) or hydrocortisone (40-60 mg/day) as replacement glucocorticoid. This regimen markedly suppressed plasma levels of DHA-S, androstenedione, estrone, and estradiol, and urinary levels of aldosterone. Of 50 patients treated, 19 (38%) demonstrated either a complete (8/19) or a partial (11/19) objective disease remission which lasted for 18.05 +/- 3.1 months (mean +/- SEM). In 10 (20%) patients, there was stabilization of disease (7.8 +/- 1.2 months), accompanied by symptomatic relief of bone pain in six (12%). There was disease progression in 20 (40%) patients. The acute side effects of aminoglutethimide therapy were significant and consisted of transient lethargy (41.5%) and a cutaneous rash (35.8%). Chronic toxicity was negligible. The medical adrenalectomy regimen of aminoglutethimide plus glucocorticoid offers a suitable alternative to surgical adrenalectomy or hypophysectomy in the management of postmenopausal patients with metastatic breast carcinoma.
Topics: Adrenal Cortex; Adrenalectomy; Aldosterone; Aminoglutethimide; Androstenedione; Bone Neoplasms; Breast Neoplasms; Drug Evaluation; Estrogens; Female; Follow-Up Studies; Humans; Hypophysectomy; Lung Neoplasms; Menopause; Middle Aged; Neoplasm Metastasis; Prolactin; Radiography; Remission, Spontaneous; Thyrotropin; Thyroxine; Time Factors
PubMed: 646874
DOI: 10.1097/00000658-197805000-00004 -
Frontiers in Genetics 2021Variability in the enzymatic activity of -acetyltransferase 2 (NAT2) is an important contributor to interindividual differences in drug responses. However, there is...
Variability in the enzymatic activity of -acetyltransferase 2 (NAT2) is an important contributor to interindividual differences in drug responses. However, there is little information on functional differences in -acetylation activities according to NAT2 phenotypes, i.e., rapid, intermediate, slow, and ultra-slow acetylators, between different substrate drugs. Here, we estimated genotypes in 990 Japanese individuals and compared the frequencies of different genotypes with those of different populations. We then calculated kinetic parameters of four NAT2 alleles (NAT24, 5, 6, and 7) for -acetylation of aminoglutethimide, diaminodiphenyl sulfone, hydralazine, isoniazid, phenelzine, procaineamide, sulfamethazine (SMZ), and sulfapyrizine. NAT25, 6, and 7 exhibited significantly reduced -acetylation activities with lower Vmax and CLint values of all drugs when compared with NAT24. Hierarchical clustering analysis revealed that 10 genotypes were categorized into three or four clusters. According to the results of metabolic experiments using SMZ as a substrate, the frequencies of ultra-slow acetylators were calculated to be 29.05-54.27% in Europeans, Africans, and South East Asians, whereas Japanese and East Asian populations showed lower frequencies (4.75 and 11.11%, respectively). Our findings will be helpful for prediction of responses to drugs primarily metabolized by NAT2.
PubMed: 33815485
DOI: 10.3389/fgene.2021.652704 -
British Journal of Cancer Feb 1985Hydroxylaminoglutethimide [3-ethyl-3-(4-hydroxylaminophenyl)piperidine-2,6-dione] (HxAG), aminoglutethimide [3-(4-aminophenyl)-3-ethylpiperidine-2,6-dione] (AG) and...
Hydroxylaminoglutethimide [3-ethyl-3-(4-hydroxylaminophenyl)piperidine-2,6-dione] (HxAG), aminoglutethimide [3-(4-aminophenyl)-3-ethylpiperidine-2,6-dione] (AG) and N-acetyl-aminoglutethimide (N-AcAG) have been quantified by high performance liquid chromatography using m-aminoglutethimide (metaAG) as the internal standard in serial 24 h urine collections from a patient on chronic AG therapy without steroid supplementation. HxAG is the product of a major AG-induced metabolic pathway since the ratio [HxAG]/[AG] rises with time. In contrast the ratio [N-AcAG]/[AG] decreases with time. A rapid, simple colorimetric assay has been used to quantify HxAG in urine from both male and female patients receiving a range of doses of AG and to show that induced metabolism is a general phenomenon even at low doses (125 mg twice daily). AG therapy is known to alter the metabolic rate and plasma half-life of a number of coadministered compounds including dexamethasone and warfarin. Clinicians should remain alerted to this phenomenon.
Topics: Aminoglutethimide; Breast Neoplasms; Chromatography, High Pressure Liquid; Colorimetry; Female; Humans; Male
PubMed: 3838134
DOI: 10.1038/bjc.1985.37 -
Environmental Health Perspectives Apr 1981Advances in two techniques have made the problem of assessing the acute and/or chronic effects of toxic agents on Leydig cell structure and testosterone synthesis and...
Advances in two techniques have made the problem of assessing the acute and/or chronic effects of toxic agents on Leydig cell structure and testosterone synthesis and secretion amenable to study. First, in vitro testicular perfusion has been perfected to a point where it closely resembles in situ testosterone secretion. Second, now it is possible to quantify the proportion of Leydig cell cytoplasm occupied by the cellular organelles which contain steroidogenic enzymes. Herein, we report that inhibition of Leydig cell steroidogenic enzymes is reflected by reduced testosterone secretion by in vitro perfused rat and rabbit testes. Moreover, the activity of specific steroidogenic reactions can be monitored by measuring the secretion of reaction substrate(s) and product(s) from in vitro perfused testes. Testosterone secretion by in vitro perfused testes from five species is highly and positively correlated with the volume density of smooth endoplasmic reticulum in Leydig cell cytoplasm. Exploitation of these findings will allow toxicologists to quantitatively assess the effect of toxicants on Leydig cell testosterone biosynthesis and secretion, to identify the specific steroidogenic enzymes affected, to assess whether the membranous environment of the steroidogenic enzymes is compromised, and perhaps even to predict the deleterious effect of a toxic agent on Leydig cell steroidogenic function from a stereological assessment of Leydig cell ultrastructure.
Topics: Aging; Aminoglutethimide; Androgens; Animals; Leydig Cells; Male; Medrogestone; Mixed Function Oxygenases; Pyridines; Rabbits; Testis; Testosterone; Tetrahydronaphthalenes
PubMed: 7238445
DOI: 10.1289/ehp.813819 -
Synthesis and biological evaluation of 16E-arylidenosteroids as cytotoxic and anti-aromatase agents.Chemical & Pharmaceutical Bulletin 2011Taking into consideration the structural requirements for cytotoxicity and aromatase inhibition, several new 16E-arylidenosteroidal derivatives have been prepared and...
Taking into consideration the structural requirements for cytotoxicity and aromatase inhibition, several new 16E-arylidenosteroidal derivatives have been prepared and evaluated for their cytotoxic and aromatase inhibitory activity. The new steroidal analogues 3, 5-8 and 11 exhibited significant cytotoxic effects when screened against three cancer cell lines, MCF-7 (breast), NCl-H460 (lung) and SF-268 central nervous system (CNS) at 100 µM and sensible cytotoxic effects subsequently in sixty cancer cell lines derived from nine cancers types (leukemia, lung, colon, CNS, melanoma, ovarian, renal, prostate and breast cancers). The imidazolyl substituted steroidal derivatives 5 and 7 exhibited strong inhibition of the aromatase enzyme with 16-[4-{3-(imidazol-1-yl)propoxy}-3-methoxybenzylidene]-5-androstene-3β,17β-diol (7) displaying 13 times more potency in comparison to aminoglutethimide.
Topics: Androstenediols; Androstenedione; Antineoplastic Agents; Aromatase; Aromatase Inhibitors; Cell Line, Tumor; Drug Screening Assays, Antitumor; Humans; Steroids
PubMed: 21372413
DOI: 10.1248/cpb.59.327