- IN VITRO ADRENAL BIOACTIVATION AND EFFECTS ON STEROID METABOLISM OF DDT, PCBs AND THEIR METABOLITES IN THE GRAY SEAL (HALICHOERUS GRYPUS)
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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.
- Lund, Bert-Ove
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- Mass spectrometry imaging for dissecting steroid intracrinology within target tissues
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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.
- Cobice, Diego F.,Logan MacKay,Goodwin, Richard J. A.,McBride, Andrew,Langridge-Smith, Patrick R.,Webster, Scott P.,Walker, Brian R.,Andrew, Ruth
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- Functional interactions of adrenodoxin with several human mitochondrial cytochrome P450 enzymes
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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.
- Barckhausen, Ian R.,Child, Stella A.,Glass, Sarah M.,Goldfarb, Margo H.,Guengerich, F. Peter,Reddish, Michael J.
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- HYDROXYSTEROID COMPOUNDS, THEIR INTERMEDIATES, PROCESS OF PREPARATION, COMPOSITION AND USES THEREOF
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The present invention relates to novel steroidal compounds of formula (I), process for preparation of the same and composition comprising these compounds.
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Page/Page column 40; 41
(2016/02/09)
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- Raw synthesis and mitochondrial function postischemic mitochondria diseases related to the lack or for use in new compd. 11β-hydroxysteroid
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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.
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Paragraph 0278
(2016/10/08)
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- NEUROACTIVE STEROIDS, COMPOSITIONS, AND USES THEREOF
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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.
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Page/Page column 87; 88
(2014/01/08)
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- Method for reducing or preventing transplant rejection in the eye and intraocular implants for use therefor
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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.
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- Scandium trifluoromethanesulfonate-catalyzed cleavage of esters bearing a coordinative group at a vicinal position
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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.
- Kajiro, Hiroshi,Mitamura, Shuichi,Mori, Atsunori,Hiyama, Tamejiro
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p. 1553 - 1560
(2007/10/03)
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- Inhibition of aldosterone formation by cortisol in rat adrenal mitochondria
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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
- Matkovic, Laura,Gomez-Sanchez, Celso E.,Lantos, Carlos P.,Cozza, Eduardo N.
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p. 447 - 452
(2007/10/02)
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- Biotransformation of corticosteroids by Penicillium decumbens ATCC 10436
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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.
- Holland, Herbert L.
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p. 646 - 649
(2007/10/02)
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- BIOSYNTHESIS OF ANDROGENS BY PHEOCHROMOCYTOMAS
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Homogenates from four adrenal pheochromocytomas converted 4-14C-labeled pregnenolone, 17-hydroxyprogesterone, and dehydroepiandrosterone into androstenedione and testosterone.In addition to these androgens, labeled pregnane substrates were also transformed into corticosteroids, as previously reported, and this conversion occurred in even higher yield.The formation of labeled metabolites of either pathway was greater in homogenates from intraadrenal pheochromocytomas than in those derived from an extraadrenal tumor, but less than in preparations of hyperplastic adrenal cortex.Incubations of subcellular fractions isolated from an adrenal pheochromocytoma showed that the enzyme activities involved in androgen formation from the radioactive substrates studied were associated with the microsomes and required exogenous cofactors.In contrast to adrenocortical tissue, chromaffin cell preparations uniformly failed to convert substrate cholesterol into either androgens or corticosteroids.The data available demonstrate the presence in chromaffin tissue of all of the enzyme activities required for the biosynthesis of androgens and corticosteroids except for those involved in the side-chain scission of cholesterol.
- Carballeira, Andres,Brown, John W.,Fishman, Lawrence M.
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p. 647 - 660
(2007/10/02)
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- Cytotoxic nucleoside-corticosteroid phosphodiesters
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Nucleotides of nucleosides or bases having known cytotoxic activity are reacted with steroids, preferably corticosteroids, to form corresponding cytotoxic nucleoside-corticosteroid phosphodiester analogues of the formula: STR1 wherein: steroid is the residue formed by removal of a hydroxyl hydrogen atom from a natural or synthetic adrenal corticosteroid containing the characteristic cyclopentanophenanthrene nucleus which is esterified to the phosphate moiety at the 21-position; sugar is a naturally occurring pentose or deoxypentose in the furanose form, preferably ribose, deoxyribose, lyxose, xylose or arabinose and especially ribose, deoxyribose or arabinose, which is esterified to the phosphate moiety at the 5'-position and covalently bonded to the heterocycle moiety at the 1'-position to form a nucleoside; and heterocycle is a purine, pyrimidine, hydrogenated pyrimidine, triazolopurine or similar nucleoside base. The conjugates exhibit an enhanced therapeutic index as compared to the parent nucleoside or base compounds, and are thus useful cytotoxic, antiviral and antineoplastic agents.
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- Differences between adrenal adenoma causing primary aldosteronism and other adrenal tissues in the incorporation of labeled steroid precursors into their products
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The incorporation and conversion of several labeled steroid precursors into their products were examined in slices of adrenal tissue from two patients with primary aldosteronism and compared with that in 'normal' adrenal tissue and adrenal tissues from a patient with Cushing's syndrome. The products of the incorporation were separated by Sephadex LH-20 column chromatography. The major products of conversion in the adenomatous tissue of primary aldosteronism were 18-hydroxycorticosterone and lesser amounts of aldosterone. Smaller amounts of 18-hydroxycorticosterone were isolated from all other adrenal tissues studied. No aldosterone could be recovered after incubating any of the adrenal tissue studied with labeled 18-hydroxy-11-deoxycorticosterone or 18-hydroxycorticosterone as precursor steroid. These in vitro results seem to suggest that there is increased 18-hydroxylation in the adenoma of primary aldosteronism compared with other tissues and that relatively more 18-hydroxycorticosterone is produced in such tissue than aldosterone.
- Usa,Ganguly,Weinberger
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p. 531 - 545
(2007/10/02)
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- Danazol Inhibits Human Adrenal 21- and 11β-Hydroxylation in vitro
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The effects of danazol on steroidogenesis in vitro in the 16-20 week old human fetal adrenal were examined by studying: 1) danazol binding to adrenal microsomal and mitochondrial cytochrome P-450, and 2) enzyme kinetics of danazol inhibition of the adrenal microsomal 21-hydroxylase and the mitochondrial 11β-hydroxylase.The addition of danazol to preparations of adrenal microsomes or mitochondria elicited a type I cytochrome P-450 binding spectrum.Danazol bound to microsomal cytochrome P-450 with a high affinity apparent spectral dissociation constant (KS) of 1 μM and with a lower affinity K'S of 10 μM.Danazol bound to mitochondrial cytochrome P-450 with a KS of 5 μM.In addition, danazol competitively inhibited the microsomal 21-hydroxylase (apparent enzymatic inhibition constant KI = 0.8 μM) and the mitrochondrial 11β-hydroxylase (KI = 3 μM).These findings demonstrate that low concentrations of danazol directly inhibit steroidogenesis in the human fetal adrenal in vitro.
- Barbieri, Robert L.,Osathanondh, Rapin,Canick, Jacob A.,Stillman, Robert J.,Ryan, Kenneth J.
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p. 251 - 263
(2007/10/02)
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- REGENERATION OF KETONES FROM SEMICARBAZONES BY LEAD TETRA-ACETATE : A NOVEL PREPARATION OF 18-HYDROXYCORTICOSTERONE
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Lead tetra-acetate in acetic acid has been used to cleave a 3-semicarbazone in a novel preparation of 18-hydroxycorticosrerone, designed to avoid strongly acidic conditions.
- Kirk, David N.,Slade, Christopher J.
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p. 651 - 654
(2007/10/02)
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