50-22-6Relevant articles and documents
IN VITRO ADRENAL BIOACTIVATION AND EFFECTS ON STEROID METABOLISM OF DDT, PCBs AND THEIR METABOLITES IN THE GRAY SEAL (HALICHOERUS GRYPUS)
Lund, Bert-Ove
, p. 911 - 918 (1994)
The irreversible binding of the DDT metabolites o, p'-DDD and MeSO2-DDE, as well as their potential to inhibit mitochondrial steroid 11β-hydroxylation in the gray seal adrenal gland, was studied. The adrenal bioactivated both o, p'-DDD and MeSO2 -DDE in vitro. The irreversible binding of o, p'-DDD was, however, 17 times higher than that of MeSO2- DDE. In both cases, the enzymes responsible for the activation resided primarily in mitochondria, and inhibitory effects of cytochrome P450 inhibitors (metyrapone and SKF 525A) and NADPH omission indicated mitochondrial P450 enzymes as responsible for the bioactivation. Forty-micromolar concentrations of o, p'-DDD and p, p'-DDT inhibited 11β-hydroxylation of glucocorticoids (10μM) by approximately 25 percent. In contrast, none of the studied compounds - MeSO2-DDE, p, p'-DDE, some PCBs, and methylsulfonyl-PCBs (40 μM) - affected the mitochondrial 11β-hydroxylase activity. Bioactivation of environmental pollutants such as DDT and PCB metabolites and inhibition of P450 11β-hydroxylase are discussed as possible reasons for the generation of the adrenocortical hyperplasia observed in Baltic seals. - Keywords: DDT; DDD; Methylsulfonyl-DDE; Seal adrenal; 11β-Hydroxylase.
Mass spectrometry imaging for dissecting steroid intracrinology within target tissues
Cobice, Diego F.,Logan MacKay,Goodwin, Richard J. A.,McBride, Andrew,Langridge-Smith, Patrick R.,Webster, Scott P.,Walker, Brian R.,Andrew, Ruth
, p. 11576 - 11584 (2013)
Steroid concentrations within tissues are modulated by intracellular enzymes. Such steroid intracrinology influences hormone-dependent cancers and obesity and provides targets for pharmacological inhibition. However, no high resolution methods exist to quantify steroids within target tissues. We developed mass spectrometry imaging (MSI), combining matrix assisted laser desorption ionization with on-tissue derivatization with Girard T and Fourier transform ion cyclotron resonance mass spectrometry, to quantify substrate and product (11-dehydrocorticosterone and corticosterone) of the glucocorticoid-amplifying enzyme 11β-HSD1. Regional steroid distribution was imaged at 150-200 μm resolution in rat adrenal gland and mouse brain sections and confirmed with collision induced dissociation/liquid extraction surface analysis. In brains of mice with 11β-HSD1 deficiency or inhibition, MSI quantified changes in subregional corticosterone/11-dehydrocorticosterone ratio, distribution of inhibitor, and accumulation of the alternative 11β-HSD1 substrate, 7-ketocholesterol. MSI data correlated well with LC-MS/MS in whole brain homogenates. MSI with derivatization is a powerful new tool to investigate steroid biology within tissues.
Functional interactions of adrenodoxin with several human mitochondrial cytochrome P450 enzymes
Barckhausen, Ian R.,Child, Stella A.,Glass, Sarah M.,Goldfarb, Margo H.,Guengerich, F. Peter,Reddish, Michael J.
, (2020/10/02)
Seven of the 57 human cytochrome P450 (P450) enzymes are mitochondrial and carry out important reactions with steroids and vitamins A and D. These seven P450s utilize an electron transport chain that includes NADPH, NADPH-adrenodoxin reductase (AdR), and adrenodoxin (Adx) instead of the diflavin NADPH-P450 reductase (POR) used by the other P450s in the endoplasmic reticulum. Although numerous studies have been published involving mitochondrial P450 systems, the experimental conditions vary considerably. We compared human Adx and bovine Adx, a commonly used component, and found very similar catalytic activities in reactions catalyzed by human P450s 11B2, 27A1, and 27C1. Binding constants of 6–200 nM were estimated for Adx binding to these P450s using microscale thermophoresis. All P450 catalytic reactions were saturated at 10 μM Adx, and higher concentrations were not inhibitory up to at least 50 μM. Collectively these studies demonstrate the tight binding of Adx (both human and bovine) to AdR and to several mitochondrial P450s and provide guidance for optimization of Adx-dependent P450 reactions.
HYDROXYSTEROID COMPOUNDS, THEIR INTERMEDIATES, PROCESS OF PREPARATION, COMPOSITION AND USES THEREOF
-
Page/Page column 40; 41, (2016/02/09)
The present invention relates to novel steroidal compounds of formula (I), process for preparation of the same and composition comprising these compounds.
Raw synthesis and mitochondrial function postischemic mitochondria diseases related to the lack or for use in new compd. 11β-hydroxysteroid
-
Paragraph 0278, (2016/10/08)
The present invention provides novel compounds of 112-hydroxy steroids and compositions and their application as pharmaceuticals for preventing or reversing injury to mitochondria, for treating or preventing diseases relating to mitochondrial dysfunction or depletion, and for inducing regeneration or restructuring of mitochondria as a means of treating diseases relating to abnormalities in mitochondrial structure and function in a human or animal subject. Also disclosed herein are methods for diagnosing injury to mitochondria and for diagnosing the success or failure of therapeutics designed to treat, prevent, or reverse injury to or depletion of mitochondria.
NEUROACTIVE STEROIDS, COMPOSITIONS, AND USES THEREOF
-
Page/Page column 87; 88, (2014/01/08)
Described herein are neuroactive steroids of the Formula (I) or a pharmaceutically acceptable salt, solvate, stereoisomer, tautomer, and/or isotopic variant thereof; wherein ----, X, Z1, Z2, R1, R2, R3, and R4 are as defined herein, provided at least one of R1, R2, R3, and X a group of the formula -OC(=O)RE1. Such compounds are envisioned, in certain embodiments, to behave as soft drugs and, in certain embodiments, as GABA modulators. The present invention also provides pharmaceutical compositions comprising a compound of the present invention and methods of use and treatment, e.g., such for inducing sedation and/or anesthesia.
Method for reducing or preventing transplant rejection in the eye and intraocular implants for use therefor
-
, (2008/06/13)
Methods for reducing or preventing transplant rejection in the eye of an individual are described, comprising: a) performing an ocular transplant procedure; and b) implanting in the eye a bioerodible drug delivery system comprising an immunosuppressive agent and a bioerodible polymer.
Scandium trifluoromethanesulfonate-catalyzed cleavage of esters bearing a coordinative group at a vicinal position
Kajiro, Hiroshi,Mitamura, Shuichi,Mori, Atsunori,Hiyama, Tamejiro
, p. 1553 - 1560 (2007/10/03)
Scandium trifluoromethanesulfonate is found to be a Lewis acid catalyst for selective cleavage of esters containing a coordinative group adjacent to an ester moiety. The reaction proceeds under weak acidic conditions at room temperature; the catalyst can be recovered and reused. Even α-acyloxy ketones are deacetylated without racemization. Selective monodeacetylation at C-10 of paclitaxel has been achieved.
Biotransformation of corticosteroids by Penicillium decumbens ATCC 10436
Holland, Herbert L.
, p. 646 - 649 (2007/10/02)
The biotransformation of a series of corticosteroids by the fungus Penicillium decumbens ATCC 10436 has been investigated. Conversion to the corresponding 5α-dihydroxteroid was observed for all the Δ4-3-ketosteroids studied with the exception of deoxycorticosterone, which was converted to a Δ14-diene. Deoxycorticosterone acetate was, however, converted to a 5α- dihydro product concomitant with ester hydrolysis. Other substrates carrying a C-21 acetoxy group were also hydrolyzed to the alcohol. In two cases (resulting from deoxycorticosterone acetate and 11-deoxycortisone) the 5α- 3-keto-product was further reduced to the 3β-alcohol. No reduction of δ14-dienes was observed.
Inhibition of aldosterone formation by cortisol in rat adrenal mitochondria
Matkovic, Laura,Gomez-Sanchez, Celso E.,Lantos, Carlos P.,Cozza, Eduardo N.
, p. 447 - 452 (2007/10/02)
In this work we confirm by a metabolic method the existence of at least two enzymes with 11β- and 18-hydroxylase activities in rat adrenal mitochondria.The method was based on the ability of cortisol (F), a foreign alternative substrate, to inhibit competitively metabolite productions from various precursors.F inhibited a) aldosterone (ALDO) production from 11-deoxycorticosterone (DOC) without affecting the yields of corticosterone (B) and 18-hydroxy-11-deoxycorticosterone (18-OHDOC); b) 18-hydroxycorticosterone and aldosterone productions from B (Ki = 2.5 +/- 0.5 μM); and c) ALDO production from 18-OHDOC.These results suggest the existence of two categories of enzymes with both 11β- and 18-hydroxylase activities, one comprising those that catalyze the conversions of DOC to B and 18-OHDOC (F-insensitive reactions ) and the other one comprising the enzymes involved in the conversions of B to 18-OHB and ALDO and that of 18-OHDOC to ALDO (F-sensitive reactions ).The cloned enzymes CYP11B1 and CYP11B2 would pertain respectively to the FIS and FS categories. - Keywords: aldosterone; adrenal; cytochrome P450; 11β,18-hydroxylases; steroidogenesis; Cortisol
