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Hennebert 2009 The-Journal-of-Steroid-Biochemistry-and-Molecular-Biology
2013
Cytochrome P4507B1 7␣-hydroxylates dehydroepiandrosterone (DHEA), epiandrosterone (EpiA) and 5␣androstane-3,17-diol (Adiol). 11-Hydroxysteroid dehydrogenase type 1 (11-HSD1) interconverts 7␣-and 7-forms. Whether the interconversion proceeds through oxido-reductive steps or epimerase activity was investigated. Experiments using [ 3 H]-labelled 7-hydroxy-DHEA, 7-hydroxy-EpiA and 7hydroxy-Adiol showed the 3 H-label to accumulate in the 7-oxo-DHEA trap but not in 7-oxo-EpiA or 7-oxo-Adiol traps. Computed models of 7-oxygenated steroids docked in the active site of 11-HSD1 either in a flipped or turned form relative to cortisone and cortisol. 7-Oxo-steroid reduction in 7␣-o r 7-hydroxylated derivatives resulted from either turned or flipped forms. 11-HSD1 incubation in H 2 18 O medium with each 7-hydroxysteroid did not incorporate 18 O in 7-hydroxylated derivatives of EpiA and Adiol independently of the cofactor used. Thus oxido-reductive steps apply for the interconversion of 7␣and 7-hydroxy-DHEA through 7-oxo-DHEA. Epimerization may proceed on the 7-hydroxylated derivatives of EpiA and Adiol through a mechanism involving the cofactor and Ser 170 . The physiopathological importance of this epimerization process is related to 7-hydroxy-EpiA production and its effects in triggering the resolution of inflammation.
Milestones on Steroids and the Nervous System: 10 Years of Basic and Translational Research
2012
During the last ten years, the conference on "Steroids and Nervous System" held in Torino (Italy) was an important international point of discussion for scientists involved in this exciting and expanding research field. The present review aimed to recapitulate the main topics that were presented through the various editions of the meeting. Two broad areas were explored: the impact of gonadal hormones on brain circuits and behaviour, and the mechanism of action of neuroactive steroids. Relationships among steroids, brain and behaviour, the sexual differentiation of the brain and the impact of gonadal hormones, the interactions of exogenous steroidal molecules (endocrine disrupters) with neural circuits and behaviour, and how gonadal steroids modulate the behaviour of GnRH neurones were the topics of several lectures and symposia during this series of meetings. At the same time, many contributions were dedicated to the biosynthetic pathways, the physiopathological relevance of neurosteroids, and the demonstration of the cellular localization of different enzymes involved in neurosteroidogenesis, the mechanisms by which steroids may exert some of their effects, both classical and non-classical action of different steroids, the role of neuroactive steroids on neurodegeneration, neuroprotection and the response of the neural tissue to injury. In these 10 years, this field has significantly advanced and neuroactive steroids have emerged as new potential therapeutic tools to counteract neurodegenerative events.
The Journal of Steroid Biochemistry and Molecular Biology
The Journal of Steroid Biochemistry and Molecular Biology, 2011
Gene regulation by steroid hormones involves genomic and non-genomic signaling pathways and the relationship between these two pathways is unknown. Genomic actions are often mediated by binding of the ligand-activated hormone receptors to hormone responsive elements (HREs) followed by recruitment of co-regulators, remodeling of chromatin and formation of the transcription initiation complex. The non-genomic effects of steroid hormones involve the rapid and transient activation of several kinase cascades often mediated by a subpopulation of "nuclear" receptors located in the cytoplasmic side of the cell membrane. The progesterone effect on breast cancer cell proliferation involves activation of the Src/Ras/Erk cascade mediated by a specific interaction between two domains of the N-terminal half of PR and the ligand-binding domain of ER␣. Unexpectedly, selective inhibition of Erk, or its target kinase Msk1, interferes with chromatin remodeling and blocks MMTV transcriptional activation. A complex of activated PR, Erk and Msk1 is recruited to promoter already 5 min after hormone treatment and phosphorylates histone H3 at serine 10, leading to displacement of HP1␥, as a requisite for recruitment of Src1, chromatin remodeling complexes (hSnf2h and Brg1) and RNA polymerase II. Thus, activation of signaling cascades in the cytoplasm is essential for chromatin remodeling and transcriptional activation of a subset of steroid hormone target genes.
Evolving concepts in the mechanism of steroid action: Current developments
American Journal of Obstetrics and Gynecology, 1987
The mechanisms of steroid action remain a poorly understood enigma. Although much effort has focused on the steroid receptor as a mediator of the steroid's effect in the cell, we are only beginning to understand the structure of steroid receptors. Development of monoclonal antibodies directed against both the steroid-binding "receptors" and receptor-associated proteins has allowed novel approaches to the problem. They were important in determining the nucleotide sequences of several receptor genes and subsequently the amino acid sequence of three receptors. Surprisingly, receptors contain amino acid sequences common to verb A , a potentiator of oncogenic transformation. Two receptor-associated proteins have been found and their relationship to the receptors suggests the possibility of additional functions of receptors in addition to binding deoxyribonucleic acid. Thus the role of the receptor in the mechanism of steroid action is evolving from the "two-step mechanism" to one that includes the recently discovered receptor-associated proteins.
The Principles, Enzymes, and Pathways of Human Steroidogenesis K E Y P O I N T S
• The conversion of cholesterol to pregnenolone is the quantitative, rate-limiting step of steroidogenesis and the site of acute regulation. • Steroidogenesis follows a specific sequence with some branch points and redundancies, and each step is either irreversible or has a strong directional preference. • Steroid formation features multiple layers of regulation, redundancy for some pathways, and multiple activities for some key enzymes. • The two major classes of steroid biosynthetic enzymes are cytochrome P450 enzymes and the hydroxysteroid dehydrogenases/reductases. • Of the steroidogenic cytochrome P450 enzymes, P450scc, P450c11, and P450c11AS are mitochondrial and use ferredoxin/ferredoxin reductase as electron transfer proteins; P450c17, P450c21, and P450aro reside in the endoplasmic reticulum and use P450-oxidoreductase as their electron transfer protein. • The hydroxysteroid dehydrogenases catalyze mechanistically reversible oxidation/ reduction reactions using NAD[P][H] cofactors; some enzymes strongly favor hydroxysteroid oxidation, and others strongly favor ketosteroid reduction in intact cells. • The 17-hydroxylase and 17,20-lyase activities of P450c17 qualitatively regulate the type of steroid hormones produced in a cell. Descargado para Anonymous User (n/a) en Universidad Nacional Autonoma de Mexico de ClinicalKey.es por Elsevier en enero 10, 2018. Para uso personal exclusivamente. No se permiten otros usos sin autorización.
The Journal of Steroid Biochemistry and Molecular Biology, 1999
In the rat brain, several steroids can be converted by speci®c enzymes to either more potent compounds or to derivatives showing new biological eects. One of the most studied enzyme is the 5a-reductase (5a-R), which acts on 3keto-D4 steroids. In males, testosterone is the main substrate and gives rise to the most potent natural androgen dihydrotestosterone. In females, progesterone is reduced to dihydroprogesterone, a precursor of allopregnanolone, a natural anxiolytic/anesthetic steroid. Other substrates are some gluco-and minero-corticoids. Two isoforms of the 5a-R, with limited degree of homology, have been cloned: 5a-R type 1 and type 2. The 5a-R type 1 possesses low anity for the various substrates and is widely distributed in the body, with the highest levels in the liver; in the brain, this isoform is expressed throughout life and does not appear to be controlled by androgens. 5a-R type 1 in the rat brain is mainly concentrated in myelin membranes, where it might be involved in the catabolism of potentially neurotoxic steroids. The 5a-R type 2 shows high anity for the various substrates, a peculiar pH optimum at acidic values and is localized in androgen-dependent structures. In the rat brain, the type 2 isoform is expressed at high levels only in the perinatal period and is controlled by androgens, at least in males. In adulthood, the type 2 gene appears to be speci®cally expressed in localised brain regions, like the hypothalamus and the hippocampus.