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Endocrine Therapies
Published in David E. Thurston, Ilona Pysz, Chemistry and Pharmacology of Anticancer Drugs, 2021
Some other hormonal agents have been previously used in the treatment of breast cancer. For example, trilostane (ModrenalTM) is a steroidogenesis inhibitor that was licensed for the treatment of Cushing’s syndrome. However, it was withdrawn from human use in the US in 1994. Trilostane was also available in the UK for the treatment of Cushing’s disease and postmenopausal breast cancer but is no longer recommended. It was well tolerated with some diarrhea and abdominal discomfort, although adrenal hypofunction was problematic and required corticosteroid replacement therapy. Also, the use of bisphosphonates in patients with metastatic breast cancer may prevent the skeletal complications of bone metastases.
Neurosteroids: metabolism and activities
Published in Barry G. Wren, Progress in the Management of the Menopause, 2020
The role of PROG in myelin repair, assessed after 2 weeks, was indicated by the decrease of thickness (number of lamellae) of myelin sheaths when trilostane, an inhibitor of 3β-HSD involved in the PREG to PROG transformation, was applied to the lesioned nerve (Figure 12b), or alternatively, when RU486 was locally delivered in order to competitively antagonize PROG action at the receptor level (Figure 12c) (as indicated before, we had detected a PROG-R immunologically and by binding studies in Schwann cells). The inhibitory action of trilostane (Figure 12b) could not be attributed to toxicity since its effect was reversed by the simultaneous administration of PROG. We could even enhance remyelination with a high dose of either PREG or PROG. In this in vivo system, the structure of the myelin sheaths formed in response to neurosteroids, as determined by electron microscopy, was morphologically normal.
Role of Steroids in the Onset of Labor
Published in Robert E. Garfield, Thomas N. Tabb, Control of Uterine Contractility, 2019
Guy Germain, Leroy Marie Josèphe, Michelle Breuiller-Fouche
The old interest in 3β-hydroxysteroid dehydrogenase/Δ4–5 isomerase (3β-HSD), which catalyzes the conversion of pregnenolone to progesterone, came from the fact that several drugs can inhibit either noncompetitively (cyanoketone) or competitively (trilostane) the 3β-HSD activity. Trilostane is effective in promoting premature parturition in sheep in late pregnancy.19 However, 3β-HSD is an ubiquitous enzyme that also converts dehydroepiandrosterone to Δ-4 androstenedione. The effect of its inhibition may therefore lead to confusing interpretations on the proper role played, respectively, by estrogens and progesterone in the support of pregnancy.
Neuroprotective and tumoricidal activities of cardiac glycosides. Could oleandrin be a new weapon against stroke and glioblastoma?
Published in International Journal of Neuroscience, 2018
İlhan Elmaci, Ebru Emekli Alturfan, Salih Cengiz, Aysel Ozpinar, Meric A. Altinoz
Hamlyn et al. discovered that an endogenous inhibitor of the Na+ pump circulates in human blood plasma which level correlates with the blood pressure [8]. Following this discovery, a number of endogenous CTS as a new type of steroid hormone were defined belonging to the group of cardenolides and bufadienolides. The Na+ pump, which exists in all cells, acts as a hormone receptor for these substances [7]. Zona glomerulosa and zona fasciculata of the adrenal cortex are proposed to store and/or synthesize endogenous ouabain and the adrenal cortex contains more ouabain than the medulla [9]. Pregnenolone and progesterone are endogenous ouabain precursors and blockage of the conversion of pregnenolone to progesterone by trilostane, an inhibitor of 3β-hydroxysteroid dehydrogenase, inhibits ouabain synthesis [10]. Mammalian cells synthesize digoxin as well; it was isolated from human urine and identified with mass spectrometry, proton NMR, and different HPLC systems [11]. Marinobufagenin (3β,5β-dihydroxy-14,14-epoxybufadienolide), discovered first in amphibians, was determined from the urine of patients with myocardial infarction [3]. Telocinobufagin, the reduced form of marinobufagenin, was also determined as an ingredient of human blood plasma by high-resolution mass spectrometry and its plasma concentration is higher than that of marinobufagenin [4]. The compound is synthesized from cholesterol in the adrenal cortex independent of the cholesterol side-chain cleavage [12].
Curcumin analogues exert potent inhibition on human and rat gonadal 3β-hydroxysteroid dehydrogenases as potential therapeutic agents: structure-activity relationship and in silico docking
Published in Journal of Enzyme Inhibition and Medicinal Chemistry, 2023
Xinyi Qiao, Lei Ye, Jialin Lu, Chengshuang Pan, Qianjin Fei, Yang Zhu, Huitao Li, Han Lin, Ren-shan Ge, Yiyan Wang
Adrenal and gonadal 3β-HSD isoform has been targeted for drug development to treat Cushing’s syndrome. For example, 3β-HSD2 inhibitor trilostane has been used as a drug to treat Cushing’s syndromes in pets and animals10–12. Human h3β-HSD2 and r3β-HSD1 belong to the short-chain alcohol dehydrogenase superfamily9 and are nicotinamide adenine dinucleotide (NAD)+-dependent enzymes, with the catalytic motif of “Ser/Thr…Tyr-X-X-X-Lys”9. They catalyses two steps of reactions, first using P5 as substrate to perform 3β-dehydrogenation reaction and then using P5’s intermediate as the substrate and reduced NAD (NADH) to carry out Δ5,4-isomeration9.
Molecular interactions of bisphenols and analogs with glucocorticoid biosynthetic pathway enzymes: an in silico approach
Published in Toxicology Mechanisms and Methods, 2018
Garima Verma, Mohemmed Faraz Khan, Wasim Akhtar, Mohammad Mumtaz Alam, Mymoona Akhter, Mohammad Shaquiquzzaman
Trilostane, the known inhibitor of 3α/20β-HSD, showed the D score of −6.558 with 3α/20β-HSD, which was found to be lower than many of the BPA analogs. The binding affinities of a few BPA analogs having lower D scores in ascending order are as follows: BP M (−7.759) < BP PH (−7.104) < BP AF (−7.012) < BP AP (−6.973) < BP C2 (−6.883) < BP P (−6.411), etc. This clearly indicates the potential of BPA analogs to inhibit 3α/20β-HSD.