Steroids lysosomes

Mechanism of Action An adrenocortical steroid that inhibits the accumulation of inflammatory cells at inflammation sites, phagocytosis, lysosomal enzyme release and synthesis, and release of mediators of inflammation. Therapeutic Effect Prevents or suppresses cell-mediated immune reactions. Decreases or prevents tissue response to inflammatory process. 

Mammalian cells acquire cholesterol either by de novo synthesis from acetyl-coen-zyme A (CoA) or via the low-density lipoprotein (LDL)-receptor-mediated uptake of LDL particles that contain cholesterol esterified with long-chain fatty acids. These LDL cholesterol esters are subsequently hydrolyzed in lysosomes, after which free cholesterol molecules become available for synthesis of membranes, steroid hormones, bile acids, or oxysterols [1]. 

The actions of non-steroidal anti-inflammatory drugs appear to be diverse. Phenylbutazone and sulfmpyrzone inhibited several effects of FMLP on PMNs increased adhesiveness, stimulation of the hexosemonophosphate shunt, lysosomal enzyme release, and formation of O These effects were explained by the ability of both phenylbutazone and sulfinpyrazone to inhibit binding of labelled FMLP to PMNs. Both were selective in that neither inhibited responses of PMNs to Csa and neither inhibited the stimulation of the hexose monophosphate shunt by latex or by opsonized Candida. The responses of PMNs to FMLP, including the release of O have also been inhibited by 5,8,11,14 eicosatetraynoic acid, an inhibitor of the metabolism of arachidonic acid h by indomethacin and by... 

Most hormones have a half-life in the blood of only a few minutes because they are cleared or metabolized very rapidly. The rapid degradation of hormones allows target cells to respond transiently. Polypeptide hormones are removed from the circulation by serum and cell surface proteases, by endocytosis followed by lysosomal degradation, and by glomerular filtration in the kidney. Steroid hormones are taken up by the liver and metabolized to inactive forms, which are excreted into the bile duct or back into the blood for removal by the kidneys. Catecholamines are metaboli-cally inactivated by O-methylation, by deamination, and by conjugation with sulfate or glucuronic acid. 

K Aikawa, T Furuchi, Y Fujimoto, H Arai, K Inoue. Structure-specific inhibition of lysosomal cholesterol transport in macrophages by various steroids. Biochim Biophys Acta 1213 127-134, 1994. 

Numerous other mechanisms, based on ultrastructural evidence, have been proposed [6] by which steroids may be secreted from their site(s) of synthesis. The steroids may be contained in secretory organelles or in lysosomes, these acting as vehicles of transport to the plasma cell membrane, where secretion occurs by... 

With the availability of new non-steroidal agents as reference compounds, the development of new in vitro assays as potential primary screens has been much facilitated. According to Mizushima 4 the thermal denaturation of protein can be inhibited by a number of antiinflammatory compounds with an order of activity roughly in agreement with their in vivo potency. As a simple model to study the stabilization of lysosomal membrauie, Brown J has described a new... 

Fourth, various modifications of a cellular pathway of CE metabolism involving plasma lipoprotein CE, apolipoprotein receptors associated with the cell surface, a lysosomal CEH, an intracellular ACAT, and a cytoplasmic, neutral CEH, can contribute to several cell functions. These functions include the synthesis of cell membranes, steroid hormones, or bile acids as well as the specialized scavenger functions of macrophages. 

Poor access via the blood-brain barrier is the major obstacle that prevents ERT from being applicable to the neuronopathic disorders. The inflammatory cascade that is mediated by CNS storage seen in the gangliosidoses for example, may respond to steroid treatment but unless the neuronal cell lysosomal burden can be reduced, this peripheral and neurological component of the phenotype could dominate the clinical outcome of disease. 

Essential non-steroidal isoprenoids, such as dolichol, prenylated proteins, heme A, and isopentenyl adenosine-containing tRNAs, are also synthesized by this pathway. In extrahepatic tissues, most cellular cholesterol is derived from de novo synthesis [3], whereas hepatocytes obtain most of their cholesterol via the receptor-mediated uptake of plasma lipoproteins, such as low-density lipoprotein (LDL). LDL is bound and internalized by the LDL receptor and delivered to lysosomes via the endocytic pathway, where hydrolysis of the core cholesteryl esters (CE) occurs (Chapter 20). The cholesterol that is released is transported throughout the cell. Normal mammalian cells tightly regulate cholesterol synthesis and LDL uptake to maintain cellular cholesterol levels within narrow limits and supply sufficient isoprenoids to satisfy metabolic requirements of the cell. Regulation of cholesterol biosynthetic enzymes takes place at the level of gene transcription, mRNA stability, translation, enzyme phosphorylation, and enzyme degradation. Cellular cholesterol levels are also modulated by a cycle of cholesterol esterification mediated by acyl-CoA cholesterol acyltransferase (ACAT) and hydrolysis of the CE, by cholesterol metabolism to bile acids and oxysterols, and by cholesterol efflux. 

The lysosomal ASs, such as ASA and ASB, exhibit optimal activity between pH 4.0 and 5.7. A second group exhibits maximum activity between pH 7 and 8, which includes ASC (also known as steroid sulfatase, STS) and PAS. The pH-rate data indicate that, depending on the enzyme, the first pif, varies from 3 to 7.1, while the second p.Afa, presumably for the general acid, can range from 6.3 to Considering the fact that ASs share similar... 

The hypothesis that contraceptive steroids might interfere with folate deconjugation in the small intestine was examined by Stephens et al. (S19). Homogenized human jejunal mucosa obtained by peroral biopsy and lysosomal preparations from guinea pig jejunum were utilized. Estradiol, estrone, and progesterone were found not to inhibit folate conjugase in these systems, or to inhibit transport of folate conjugase across lysosomal membranes. 

The clearance of released hormone from the circulation is critical for the regulation of hormone concentration. The rate of clearance may vary from a few minutes for polypeptide hormones, to a few hours for steroid and glycoprotein hormones, to days for thyroid hormones. The peptide hormones are cleared from the circulation mostly by proteolytic mechanisms in lysosomes after their uptake by cells through binding to cell-surface receptors and nonreceptor hormone-binding sites. Steroid hormones are bound to carrier proteins in the blood as mentioned above. Binding to... 

The enzymes required for steroid hormone biosynthesis must be synthesized or activated when the cell is stimulated e.g. corticotropin causes cholesterol to be converted into ucocorticoids in the adrenals. Steroid H. are not stored the appropriate enzyme system can be rapidly activated and deactivated. Cells which produce steroid H. have large Golgi apparatuses, much smooth endoplasmic reticulum, lipid droplets and lysosomes. 

On the basis of studies of the effect of excessive doses of vitamin A on culture bones and on the tail of Xenopus laevis, a theory has been put forward suggesting that vitamin A acts by rupturing lysosomes and by releasing hydrolytic enzymes in the media. In vitro experiments done in Dingle s laboratory [112, 113] and in De Duve s laboratory [114], where the hydrolases were released under the influence of vitamin A, are often called upon to support this theory. This theory meets with a number of serious objections (1) the release of a large number of hydrolases can hardly be reconciled with the effect of the vitamin on mucus synthesis and steroid hormone biosynthesis and (2) the experiments done in vivo on the Xenopus laevis were carried out with doses of vitamin A that killed 30% of the larvae, so that much of the effect may be due to necrosis rather than to a specific effect of the vitamin. Similar objections can be made with respect to experiments done in vitro with organ culture. The validity of the interpretation of an effect of vitamin A on the isolated particles is discussed in more detail in the section on cellular necrosis. 

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