Abstract:
:Abiraterone blocks androgen synthesis and prolongs survival in patients with castration-resistant prostate cancer, which is otherwise driven by intratumoral androgen synthesis. Abiraterone is metabolized in patients to Δ(4)-abiraterone (D4A), which has even greater anti-tumour activity and is structurally similar to endogenous steroidal 5α-reductase substrates, such as testosterone. Here, we show that D4A is converted to at least three 5α-reduced and three 5β-reduced metabolites in human serum. The initial 5α-reduced metabolite, 3-keto-5α-abiraterone, is present at higher concentrations than D4A in patients with prostate cancer taking abiraterone, and is an androgen receptor agonist, which promotes prostate cancer progression. In a clinical trial of abiraterone alone, followed by abiraterone plus dutasteride (a 5α-reductase inhibitor), 3-keto-5α-abiraterone and downstream metabolites were depleted by the addition of dutasteride, while D4A concentrations rose, showing that dutasteride effectively blocks production of a tumour-promoting metabolite and permits D4A accumulation. Furthermore, dutasteride did not deplete the three 5β-reduced metabolites, which were also clinically detectable, demonstrating the specific biochemical effects of pharmacological 5α-reductase inhibition on abiraterone metabolism. Our findings suggest a previously unappreciated and biochemically specific method of clinically fine-tuning abiraterone metabolism to optimize therapy.
journal_name
Naturejournal_title
Natureauthors
Li Z,Alyamani M,Li J,Rogacki K,Abazeed M,Upadhyay SK,Balk SP,Taplin ME,Auchus RJ,Sharifi Ndoi
10.1038/nature17954subject
Has Abstractpub_date
2016-05-26 00:00:00pages
547-51issue
7604eissn
0028-0836issn
1476-4687pii
nature17954journal_volume
533pub_type
杂志文章相关文献
NATURE文献大全abstract::Intestinal parasites are common in man and animals and can cause severe disease. Knowledge of immunity to such infections is limited and comes largely from studies using laboratory host-parasite systems. Understanding how immunity can operate, and why it often does not, is not only of intrinsic interest but necessary ...
journal_title:Nature
pub_type: 杂志文章
doi:10.1038/273617a0
更新日期:1978-06-22 00:00:00
abstract::Duchenne muscular dystrophy (DMD) is an X-linked recessive disorder which affects approximately 1 in 3,300 males, making it the most common of the neuromuscular dystrophies. The biochemical basis of the disease is unknown and as yet no effective treatment is available. A small number of females are also affected with ...
journal_title:Nature
pub_type: 杂志文章
doi:10.1038/318672a0
更新日期:1985-12-19 00:00:00
abstract::Dopamine modulates medial prefrontal cortex (mPFC) activity to mediate diverse behavioural functions1,2; however, the precise circuit computations remain unknown. One potentially unifying model by which dopamine may underlie a diversity of functions is by modulating the signal-to-noise ratio in subpopulations of mPFC ...
journal_title:Nature
pub_type: 杂志文章
doi:10.1038/s41586-018-0682-1
更新日期:2018-11-01 00:00:00
abstract::It has long been contentious whether the large representation of the fovea in the primate visual cortex (V1) indicates a selective magnification of this part of the retina, or whether it merely reflects the density of retinal ganglion cells. The measurement of the retinal ganglion-cell density is complicated by latera...
journal_title:Nature
pub_type: 杂志文章
doi:10.1038/341643a0
更新日期:1989-10-19 00:00:00
abstract::Zika virus (ZIKV) is a flavivirus that is responsible for the current epidemic in Brazil and the Americas. ZIKV has been causally associated with fetal microcephaly, intrauterine growth restriction, and other birth defects in both humans and mice. The rapid development of a safe and effective ZIKV vaccine is a global ...
journal_title:Nature
pub_type: 杂志文章
doi:10.1038/nature18952
更新日期:2016-08-25 00:00:00
abstract::Pathfinding by growing axons in the developing nervous system may be guided by gradients of extracellular guidance factors. Analogous to the process of chemotaxis in microorganisms, we found that axonal growth cones of cultured Xenopus spinal neurons exhibit adaptation during chemotactic migration, undergoing consecut...
journal_title:Nature
pub_type: 杂志文章
doi:10.1038/nature745
更新日期:2002-05-23 00:00:00
abstract::Planetary aurorae are formed by energetic charged particles streaming along the planet's magnetic field lines into the upper atmosphere from the surrounding space environment. Earth's main auroral oval is formed through interactions with the solar wind, whereas that at Jupiter is formed through interactions with plasm...
journal_title:Nature
pub_type: 杂志文章
doi:10.1038/nature07077
更新日期:2008-06-19 00:00:00
abstract::The toxicity of misfolded proteins and mitochondrial dysfunction are pivotal factors that promote age-associated functional neuronal decline and neurodegenerative disease. Accordingly, neurons invest considerable cellular resources in chaperones, protein degradation, autophagy and mitophagy to maintain proteostasis an...
journal_title:Nature
pub_type: 杂志文章
doi:10.1038/nature21362
更新日期:2017-02-16 00:00:00
abstract::The nature and length scales of charge screening in complex oxides are fundamental to a wide range of systems, spanning ceramic voltage-dependent resistors (varistors), oxide tunnel junctions and charge ordering in mixed-valence compounds. There are wide variations in the degree of charge disproportionation, length sc...
journal_title:Nature
pub_type: 杂志文章
doi:10.1038/nature00977
更新日期:2002-09-26 00:00:00
abstract::The Earth's convecting upper mantle can be viewed as comprising three main reservoirs, beneath the Pacific, Atlantic and Indian oceans. Because of the uneven global distribution and migration of ridges and subduction zones, the surface area of the Pacific reservoir is at present contracting at about 0.6 km2 x y(r-1), ...
journal_title:Nature
pub_type: 杂志文章
doi:10.1038/35068542
更新日期:2001-03-22 00:00:00
abstract::The overexpression of defined transcription factors in somatic cells results in their reprogramming into induced pluripotent stem (iPS) cells. The extremely low efficiency and slow kinetics of in vitro reprogramming suggest that further rare events are required to generate iPS cells. The nature and identity of these e...
journal_title:Nature
pub_type: 杂志文章
doi:10.1038/nature08285
更新日期:2009-08-27 00:00:00
abstract::Drosophila mutants transformed with a chimaeric gene that expresses the ocellar visual pigment in the major class of photoreceptor cells of the retina were used to investigate the properties of this minor pigment. The photoreceptor cells in which this opsin was misexpressed showed new spectral characteristics and phys...
journal_title:Nature
pub_type: 杂志文章
doi:10.1038/333737a0
更新日期:1988-06-23 00:00:00
abstract::Somatic hypermutation introduces point mutations into immunoglobulin genes in germinal centre B cells during an immune response. The reaction is initiated by cytosine deamination by the activation-induced deaminase (AID) and completed by error-prone processing of the resulting uracils by mismatch and base excision rep...
journal_title:Nature
pub_type: 杂志文章
doi:10.1038/nature06547
更新日期:2008-02-14 00:00:00
abstract::PIWI-interacting RNAs (piRNAs) silence transposons to maintain genome integrity in animal germ lines. piRNAs are classified as primary and secondary piRNAs, depending on their biogenesis machinery. Primary piRNAs are processed from long non-coding RNA precursors transcribed from piRNA clusters in the genome through th...
journal_title:Nature
pub_type: 杂志文章
doi:10.1038/nature11509
更新日期:2012-11-08 00:00:00
abstract::The T-cell receptor (TCR) repertoire is selected in the thymus after rearrangement of genes encoding TCR alpha and beta chains. Selection is based on the recognition by newly emergent T cells of self-ligands associated with molecules of the major histocompatibility complex: some combinations result in positive selecti...
journal_title:Nature
pub_type: 杂志文章
doi:10.1038/349531a0
更新日期:1991-02-07 00:00:00
abstract::Soft machines are a promising design paradigm for human-centric devices1,2 and systems required to interact gently with their environment3,4. To enable soft machines to respond intelligently to their surroundings, compliant sensory feedback mechanisms are needed. Specifically, soft alternatives to strain gauges-with h...
journal_title:Nature
pub_type: 杂志文章
doi:10.1038/s41586-020-2892-6
更新日期:2020-11-01 00:00:00
abstract::Throughout the latter half of this century, the development and spread of resistance to most front-line antimalarial compounds used in the prevention and treatment of the most severe form of human malaria has given cause for grave clinical concern. Polymorphisms in pfmdr1, the gene encoding the P-glycoprotein homologu...
journal_title:Nature
pub_type: 杂志文章
doi:10.1038/35002615
更新日期:2000-02-24 00:00:00
abstract::Arising from C. J. Phiel, C. A. Wilson, V. M.-Y. Lee & P. S. Klein 423, 435-439 (2003)A major unresolved issue in Alzheimer's disease is identifying the mechanisms that regulate proteolytic processing of amyloid precursor protein (APP)-glycogen synthase kinase-3 (GSK-3) isozymes are thought to be important in this re...
journal_title:Nature
pub_type: 评论,杂志文章
doi:10.1038/nature10615
更新日期:2011-12-07 00:00:00
abstract::Mutations or amplification of the MET proto-oncogene are involved in the pathogenesis of several tumours, which rely on the constitutive engagement of this pathway for their growth and survival. However, MET is expressed not only by cancer cells but also by tumour-associated stromal cells, although its precise role in...
journal_title:Nature
pub_type: 杂志文章
doi:10.1038/nature14407
更新日期:2015-06-18 00:00:00
abstract::The intracellular pathogen Legionella pneumophila modulates the activity of host GTPases to direct the transport and assembly of the membrane-bound compartment in which it resides. In vitro studies have indicated that the Legionella protein DrrA post-translationally modifies the GTPase Rab1 by a process called AMPylat...
journal_title:Nature
pub_type: 杂志文章
doi:10.1038/nature10335
更新日期:2011-08-07 00:00:00
abstract::T lymphocytes are predisposed to recognition of foreign protein fragments bound to cell-surface molecules encoded by the major histocompatibility complex (MHC). There is now compelling evidence that this specificity is a consequence of a selection process operating on developing T lymphocytes in the thymus. As a resul...
journal_title:Nature
pub_type: 杂志文章
doi:10.1038/341746a0
更新日期:1989-10-26 00:00:00
abstract::Tumour necrosis factor is a trimeric molecule, each subunit of which consists of an antiparallel beta-sandwich. Individual subunits from the trimer by a novel edge-to-face packing of beta-sheets. A comparison of the subunit fold with that of other proteins reveals a remarkable similarity to the 'jelly-roll' structural...
journal_title:Nature
pub_type: 杂志文章
doi:10.1038/338225a0
更新日期:1989-03-16 00:00:00
abstract::The application of a sufficiently strong magnetic field to a superconductor will, in general, destroy the superconducting state. Two mechanisms are responsible for this. The first is the Zeeman effect, which breaks apart the paired electrons if they are in a spin-singlet (but not a spin-triplet) state. The second is t...
journal_title:Nature
pub_type: 杂志文章
doi:10.1038/35073531
更新日期:2001-04-19 00:00:00
abstract::Gradual accumulation of evidence is thought to be fundamental for decision-making, and its neural correlates have been found in several brain regions. Here we develop a generalizable method to measure tuning curves that specify the relationship between neural responses and mentally accumulated evidence, and apply it t...
journal_title:Nature
pub_type: 杂志文章
doi:10.1038/nature14066
更新日期:2015-04-09 00:00:00
abstract::Connectivity in the cortex is organized at multiple scales, suggesting that scale-dependent correlated activity is particularly important for understanding the behaviour of sensory cortices and their function in stimulus encoding. We analysed the scale-dependent structure of cortical interactions by using maximum entr...
journal_title:Nature
pub_type: 杂志文章
doi:10.1038/nature09178
更新日期:2010-07-29 00:00:00
abstract::An analysis of 15 protein structures indicates: First, the loss of accessible surface area by monomeric proteins on folding-proportional to hydrophobic energy-is a simple function of molecular weight; second, the proportion of polar groups forming intramolecular hydrogen bonds is constant; and third, protein interiors...
journal_title:Nature
pub_type: 杂志文章
doi:10.1038/254304a0
更新日期:1975-03-27 00:00:00
abstract::Electronic devices have advanced from their heavy, bulky origins to become smart, mobile appliances. Nevertheless, they remain rigid, which precludes their intimate integration into everyday life. Flexible, textile and stretchable electronics are emerging research areas and may yield mainstream technologies. Rollable ...
journal_title:Nature
pub_type: 杂志文章
doi:10.1038/nature12314
更新日期:2013-07-25 00:00:00
abstract::The mouse major transplantation antigens H-2K, H-2D and H-2L are highly polymorphic cell-surface glycoproteins which may serve as recognition elements in cell-cell interactions. Each antigen possesses a number of alloantigenic determinants defined by antisera of various specificities. Recently, monoclonal antibodies h...
journal_title:Nature
pub_type: 杂志文章
doi:10.1038/300755a0
更新日期:1982-12-23 00:00:00
abstract::During the subduction of oceanic lithosphere, water is liberated from minerals by progressive dehydration reactions and is thought to be critical to several geologically important processes such as island-arc volcanism, intermediate-depth seismicity and chemical exchange between the subducting lithosphere and mantle. ...
journal_title:Nature
pub_type: 杂志文章
doi:10.1038/35048555
更新日期:2000-12-14 00:00:00
abstract::It has long been known that the 5' to 3' polarity of DNA synthesis results in both a leading and lagging strand at all replication forks. Until now, however, there has been no evidence that leading or lagging strands are spatially organized in any way within a cell. Here we show that chromosome segregation in Escheric...
journal_title:Nature
pub_type: 杂志文章
doi:10.1038/nature07282
更新日期:2008-10-30 00:00:00