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73-432: 1TQN , 1W0E , 1W0F , 1W0G , 2J0D , 2V0M , 3NXU , 3TJS , 3UA1 , 4I3Q , 4I4G , 4I4H , 4K9T , 4K9U , 4K9V , 4K9W , 4K9X , 4NY4 , 5A1P , 5A1R , 4D6Z , 4D75 , 4D78 , 4D7D 1576 n/a ENSG00000160868 n/a P08684 n/a NM_001202855 NM_001202856 NM_001202857 NM_017460 n/a NP_001189784 NP_059488 n/a Cytochrome P450 3A4 (abbreviated CYP3A4 ) ( EC 1.14.13.97 )

146-403: A 5-fold benzylation of 7-BFC in the presence of the hepatotoxic secondary bile acid lithocholic acid . This change in consequence contributes to an increased human defense against cholestasis . Fetuses do not express CYP3A4 in their liver tissue, but rather CYP3A7 ( EC 1.14.14.1 ), which acts on a similar range of substrates. CYP3A4 increases to approximately 40% of adult levels in

219-477: A class of corticosteroids , which are a class of steroid hormones . Glucocorticoids are corticosteroids that bind to the glucocorticoid receptor that is present in almost every vertebrate animal cell. The name "glucocorticoid" is a portmanteau ( gluco se + cort ex + ster oid ) and is composed from its role in regulation of glucose metabolism , synthesis in the adrenal cortex , and its steroidal structure (see structure below). Glucocorticoids are part of

292-427: A dose that provides approximately the same glucocorticoid effects as normal cortisol production; this is referred to as physiologic, replacement, or maintenance dosing. This is approximately 6–12 mg/m /day of hydrocortisone (m refers to body surface area (BSA), and is a measure of body size; an average man's BSA is 1.9 m ). Glucocorticoids cause immunosuppression , and the therapeutic component of this effect

365-491: A fatal interaction with drugs like astemizole or terfenadine . The effect of grapefruit juice with regard to drug absorption was originally discovered in 1989. The first published report on grapefruit drug interactions was in 1991 in the Lancet entitled "Interactions of Citrus Juices with Felodipine and Nifedipine ", and was the first reported food-drug interaction clinically. The effects of grapefruit last from 3–7 days, with

438-445: A few days begins to produce suppression of the patient's adrenal glands suppressing hypothalamic corticotropin-releasing hormone (CRH) leading to suppressed production of adrenocorticotropic hormone (ACTH) by the anterior pituitary. With prolonged suppression, the adrenal glands atrophy (physically shrink), and can take months to recover full function after discontinuation of the exogenous glucocorticoid. During this recovery time,

511-436: A lesser extent, after treatment, a condition known as " steroid dementia ". Glucocorticoids could act centrally, as well as peripherally, to assist in the normalization of extracellular fluid volume by regulating body's action to atrial natriuretic peptide (ANP). Centrally, glucocorticoids could inhibit dehydration-induced water intake; peripherally, glucocorticoids could induce a potent diuresis. Glucocorticoids bind to

584-600: A multitude of less-dramatic physiologic roles for glucocorticoids. Glucocorticoids have multiple effects on fetal development. An important example is their role in promoting maturation of the lung and production of the surfactant necessary for extrauterine lung function. Mice with homozygous disruptions in the corticotropin -releasing hormone gene (see below) die at birth due to pulmonary immaturity. In addition, glucocorticoids are necessary for normal brain development, by initiating terminal maturation, remodeling axons and dendrites, and affecting cell survival and may also play

657-491: A role in hippocampal development . Glucocorticoids stimulate the maturation of the Na /K /ATPase, nutrient transporters, and digestion enzymes, promoting the development of a functioning gastro-intestinal system. Glucocorticoids also support the development of the neonate's renal system by increasing glomerular filtration. Glucocorticoids act on the hippocampus , amygdala , and frontal lobes . Along with adrenaline , these enhance

730-892: A significant impact on vigilance ( attention deficit disorder ) and cognition (memory). This appears to follow the Yerkes-Dodson curve , as studies have shown circulating levels of glucocorticoids vs. memory performance follow an upside-down U pattern, much like the Yerkes-Dodson curve. For example, long-term potentiation (LTP; the process of forming long-term memories) is optimal when glucocorticoid levels are mildly elevated, whereas significant decreases of LTP are observed after adrenalectomy (low-glucocorticoid state) or after exogenous glucocorticoid administration (high-glucocorticoid state). Elevated levels of glucocorticoids enhance memory for emotionally arousing events, but lead more often than not to poor memory for material unrelated to

803-416: A transcript variant of CYP3A4. Alternatively-spliced transcript variants encoding different isoforms have been identified. CYP3A4 is a member of the cytochrome P450 superfamily of enzymes . The cytochrome P450 proteins are monooxygenases that catalyze many reactions involved in drug metabolism and synthesis of steroids (including cholesterol ), and other lipids . The CYP3A4 protein localizes to

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876-622: A wide range of activities that include growth stimulation in breast and other types of cancers (see 12-hydroxyeicosatetraenoic acid ). The CYP3A4 gene exhibits a much more complicated upstream regulatory region in comparison with its paralogs . This increased complexity renders the CYP3A4 gene more sensitive to endogenous and exogenous PXR and CAR ligands, instead of relying on gene variants for wider specificity. Chimpanzee and human CYP3A4 are highly conserved in metabolism of many ligands , although four amino acids positively selected in humans led to

949-424: A wide range of effects, including, for example: The opposite mechanism is called transcriptional repression, or transrepression . The classical understanding of this mechanism is that activated glucocorticoid receptor binds to DNA in the same site where another transcription factor would bind, which prevents the transcription of genes that are transcribed via the activity of that factor. While this does occur,

1022-447: Is a cage-controlled radical method ("oxygen rebound"), and the second involves a concerted mechanism that does not utilize a radical intermediate but instead acts very quickly via a " radical clock ". In 1998, various researchers showed that grapefruit juice, and grapefruit in general, is a potent inhibitor of CYP3A4, which can affect the metabolism of a variety of drugs, increasing their bioavailability . In some cases, this can lead to

1095-429: Is an important enzyme in the body, mainly found in the liver and in the intestine, which in humans is encoded by CYP3A4 gene. It oxidizes small foreign organic molecules ( xenobiotics ), such as toxins or drugs, so that they can be removed from the body. It is highly homologous to CYP3A5 , another important CYP3A enzyme. While many drugs are deactivated by CYP3A4, there are also some drugs that are activated by

1168-403: Is complicated. Dexamethasone decreases IFN-gamma stimulated Fc gamma RI expression in neutrophils while conversely causing an increase in monocytes . Glucocorticoids may also decrease the expression of Fc receptors in macrophages, but the evidence supporting this regulation in earlier studies has been questioned. The effect of Fc receptor expression in macrophages is important since it

1241-642: Is different from the 'FORMAT NUMBER' Oxidation /reduction reactions; transfer of H and O atoms or electrons from one substance to another Similarity between enzymatic reactions can be calculated by using bond changes, reaction centres or substructure metrics (formerly EC-BLAST], now the EMBL-EBI Enzyme Portal). Before the development of the EC number system, enzymes were named in an arbitrary fashion, and names like old yellow enzyme and malic enzyme that give little or no clue as to what reaction

1314-406: Is likely to be a function of the rate of enterocyte renewal ; an indirect approach based on the recovery of activity following exposure to grapefruit juice yields measurements in the 12- to 33-hour range. Due to membrane-bound CYP3A4's natural propensity to conglomerate, it has historically been difficult to study drug binding in both solution and on surfaces. Co-crystallization is difficult since

1387-412: Is mainly the decreases in the function and numbers of lymphocytes , including both B cells and T cells . The major mechanism for this immunosuppression is through inhibition of nuclear factor kappa-light-chain-enhancer of activated B cells ( NF-κB ). NF-κB is a critical transcription factor involved in the synthesis of many mediators (i.e., cytokines) and proteins (i.e., adhesion proteins) that promote

1460-673: Is more prominent in immature T cells still inside in the thymus, but peripheral T cells are also affected. The exact mechanism regulating this glucocorticoid sensitivity lies in the Bcl-2 gene. Glucocorticoids also suppress the humoral immunity , thereby causing a humoral immune deficiency . Glucocorticoids cause B cells to express smaller amounts of IL-2 and of IL-2 receptors . This diminishes both B cell clone expansion and antibody synthesis. The diminished amounts of IL-2 also cause fewer T lymphocyte cells to be activated. The effect of glucocorticoids on Fc receptor expression in immune cells

1533-662: Is necessary for the phagocytosis of opsonised cells. This is because Fc receptors bind antibodies attached to cells targeted for destruction by macrophages. Glucocorticoids are potent anti-inflammatories, regardless of the inflammation's cause; their primary anti-inflammatory mechanism is lipocortin-1 (annexin-1) synthesis. Lipocortin-1 both suppresses phospholipase A2 , thereby blocking eicosanoid production, and inhibits various leukocyte inflammatory events ( epithelial adhesion , emigration , chemotaxis , phagocytosis , respiratory burst , etc.). In other words, glucocorticoids not only suppress immune response, but also inhibit

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1606-403: Is not activated by rifampicin and human PXR is not activated by pregnenolone 16α-carbonitrile In order to facilitate study of CYP3A4 functional pathways in vivo, mouse strains have been developed using transgenes in order to produce null/human CYP3A4 and PXR crosses. Although humanized hCYP3A4 mice successfully expressed the enzyme in their intestinal tract, low levels of hCYP3A4 were found in

1679-669: Is released when a glucocorticoid binds to glucocorticoid receptor, and phosphorylates a protein that in turn displaces an adaptor protein from a receptor important in inflammation, epidermal growth factor , reducing its activity, which in turn results in reduced creation of arachidonic acid – a key proinflammatory molecule. This is one mechanism by which glucocorticoids have an anti-inflammatory effect. A variety of synthetic glucocorticoids, some far more potent than cortisol, have been created for therapeutic use. They differ in both pharmacokinetics (absorption factor, half-life, volume of distribution, clearance) and pharmacodynamics (for example

1752-458: Is sometimes followed by dehydrogenation, leading to more complex metabolites. An example of a molecule that undergoes more than one reaction due to CYP3A4 includes tamoxifen , which is hydroxylated to 4-hydroxy-tamoxifen and then dehydrated to 4-hydroxy-tamoxifen quinone methide. Two mechanisms have been proposed as the primary pathway of hydroxylation in P450 enzymes. The first pathway suggested

1825-479: Is the most common and the most versatile one. Like all members of this family, it is a hemoprotein , i.e. a protein containing a heme group with an iron atom. In humans, the CYP3A4 protein is encoded by the CYP3A4 gene . This gene is part of a cluster of cytochrome P450 genes on chromosome 7q22.1 . Previously another CYP3A gene, CYP3A3, was thought to exist; however, it is now thought that this sequence represents

1898-740: Is the name used for pharmaceutical preparations of cortisol. The data below refer to oral administration. Oral potency may be less than parenteral potency because significant amounts (up to 50% in some cases) may not reach the circulation. Fludrocortisone acetate and deoxycorticosterone acetate are, by definition, mineralocorticoids rather than glucocorticoids, but they do have minor glucocorticoid potency and are included in this table to provide perspective on mineralocorticoid potency. Glucocorticoids may be used in low doses in adrenal insufficiency . In much higher doses, oral or inhaled glucocorticoids are used to suppress various allergic , inflammatory , and autoimmune disorders. Inhaled glucocorticoids are

1971-709: The CYP3A4 gene, it has been found that this does not translate into significant interindividual variability in vivo . It can be supposed that this may be due to the induction of CYP3A4 on exposure to substrates. CYP3A4 alleles that have been reported to have minimal function compared to wild-type include CYP3A4*6 (an A17776 insertion) and CYP3A4*17 (F189S). Both of these SNPs led to decreased catalytic activity with certain ligands, including testosterone and nifedipine in comparison to wild-type metabolism. By contrast, CYP3A4*1G allele has more potent enzymatic activity compared to CYP3A4*1A (the wild-type allele). Variability in CYP3A4 function can be determined noninvasively by

2044-526: The XREM region of the CYP3A4 gene. XREM is a regulatory region of the CYP3A4 gene, and binding causes a cooperative interaction with proximal promoter regions of the gene, resulting in increased transcription and expression of CYP3A4. Activation of the PXR/RXR heterodimer initiates transcription of the CYP3A4 promoter region and gene. Ligand binding increases when in the presence of CYP3A4 ligands, such as in

2117-558: The adrenal cortex ), but is often used as a synonym for "glucocorticoid". Glucocorticoids are chiefly produced in the zona fasciculata of the adrenal cortex , whereas mineralocorticoids are synthesized in the zona glomerulosa . Cortisol (or hydrocortisone) is the most important human glucocorticoid. It is essential for life , and it regulates or supports a variety of important cardiovascular , metabolic , immunologic , and homeostatic functions. Increases in glucocorticoid concentrations are an integral part of stress response and are

2190-539: The endoplasmic reticulum , and its expression is induced by glucocorticoids and some pharmacological agents. Cytochrome P450 enzymes metabolize approximately 60% of prescribed drugs, with CYP3A4 responsible for about half of this metabolism; substrates include acetaminophen (paracetamol), codeine , ciclosporin (cyclosporin), diazepam , erythromycin , and chloroquine . The enzyme also metabolizes some steroids and carcinogens . Most drugs undergo deactivation by CYP3A4, either directly or by facilitated excretion from

2263-410: The erythromycin breath test (ERMBT). The ERMBT estimates in vivo CYP3A4 activity by measuring the radiolabelled carbon dioxide exhaled after an intravenous dose of (C- N -methyl)- erythromycin . CYP3A4 is induced by a wide variety of ligands . These ligands bind to the pregnane X receptor (PXR). The activated PXR complex forms a heterodimer with the retinoid X receptor (RXR), which binds to

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2336-435: The feedback mechanism in the immune system , which reduces certain aspects of immune function, such as inflammation . They are therefore used in medicine to treat diseases caused by an overactive immune system , such as allergies , asthma , autoimmune diseases , and sepsis . Glucocorticoids have many diverse effects such as pleiotropy , including potentially harmful side effects . They also interfere with some of

2409-727: The International Congress of Biochemistry in Brussels set up the Commission on Enzymes under the chairmanship of Malcolm Dixon in 1955. The first version was published in 1961, and the Enzyme Commission was dissolved at that time, though its name lives on in the term EC Number . The current sixth edition, published by the International Union of Biochemistry and Molecular Biology in 1992 as

2482-416: The abnormal mechanisms in cancer cells , so they are used in high doses to treat cancer. This includes inhibitory effects on lymphocyte proliferation, as in the treatment of lymphomas and leukemias , and the mitigation of side effects of anticancer drugs . Glucocorticoids affect cells by binding to the glucocorticoid receptor . The activated glucocorticoid receptor-glucocorticoid complex up-regulates

2555-502: The advantage of only affecting the targeted area, thereby reducing side effects or potential interactions. In this case, the main compounds used are beclometasone , budesonide , fluticasone , mometasone and ciclesonide . In rhinitis, sprays are used. For asthma, glucocorticoids are administered as inhalants with a metered-dose or dry powder inhaler . In rare cases, symptoms of radiation induced thyroiditis has been treated with oral glucocorticoids. Glucocorticoids can be used in

2628-670: The body's immune system. Glucocorticoid effects may be broadly classified into two major categories: immunological and metabolic . In addition, glucocorticoids play important roles in fetal development and body fluid homeostasis. Glucocorticoids function via interaction with the glucocorticoid receptor: Glucocorticoids are also shown to play a role in the development and homeostasis of T lymphocytes . This has been shown in transgenic mice with either increased or decreased sensitivity of T cell lineage to glucocorticoids. The name "glucocorticoid" derives from early observations that these hormones were involved in glucose metabolism . In

2701-427: The body. Also, many substances are bioactivated by CYP3A4 to form their active compounds, and many protoxins are toxicated into their toxic forms (see table below for examples) . CYP3A4 also possesses epoxygenase activity in that it metabolizes arachidonic acid to epoxyeicosatrienoic acids (EETs), i.e. (±)-8,9-, (±)-11,12-, and (±)-14,15-epoxyeicosatrienoic acids. EETs have a wide range of activities including

2774-447: The capacity of mineralocorticoid activity: retention of sodium (Na ) and water ; renal physiology ). Because they permeate the intestines easily, they are administered primarily per os ( by mouth ), but also by other methods, such as topically on skin . More than 90% of them bind different plasma proteins , though with a different binding specificity. Endogenous glucocorticoids and some synthetic corticoids have high affinity to

2847-420: The case of the histamine H 1 -receptor antagonist terfenadine . Recently CYP3A4 has also been identified in the brain, but its role in the central nervous system is still unknown. Cytochrome P450 enzymes perform an assortment of modifications on a variety of ligands , utilizing its large active site and its ability to bind more than one substrate at a time to perform complicated chemical alterations in

2920-480: The class. The substrates of CYP3A4 are: Inhibitors of CYP3A4 are classified by potency : The inhibitors of CYP3A4 are the following substances. Strong and moderate CYP3A4 inducers are drugs that decrease the AUC of sensitive substrates of a given pathway where CYP3A4 is involved by ≥80 percent and ≥50 to <80 percent, respectively. Weak inducers decrease the AUC by ≥20 to <50 percent. The inducers of CYP3A4 are

2993-531: The cytosolic glucocorticoid receptor , a type of nuclear receptor that is activated by ligand binding. After a hormone binds to the corresponding receptor, the newly formed complex translocates itself into the cell nucleus , where it binds to glucocorticoid response elements in the promoter region of the target genes resulting in the regulation of gene expression . This process is commonly referred to as transcriptional activation, or transactivation . The proteins encoded by these up-regulated genes have

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3066-646: The elaboration of selectively acting glucocorticoid drugs. Side effects include: In high doses, hydrocortisone (cortisol) and those glucocorticoids with appreciable mineralocorticoid potency can exert a mineralocorticoid effect as well, although in physiologic doses this is prevented by rapid degradation of cortisol by 11β-hydroxysteroid dehydrogenase isoenzyme 2 ( 11β-HSD2 ) in mineralocorticoid target tissues. Mineralocorticoid effects can include salt and water retention, extracellular fluid volume expansion, hypertension , potassium depletion, and metabolic alkalosis . Glucocorticoids cause immunosuppression , decreasing

3139-425: The enzyme's extensive presence in the intestinal mucosa, the enzyme has shown sensitivity to starvation symptoms and is upregulated in defense of adverse effects. Indeed, in fatheaded minnows, unfed female fish were shown to have increased PXR and CYP3A4 expression, and displayed a more pronounced response to xenobiotic factors after exposure after several days of starvation. By studying animal models and keeping in mind

3212-412: The enzyme. Some substances, such as some drugs and furanocoumarins present in grapefruit juice, interfere with the action of CYP3A4. These substances will, therefore, either amplify or weaken the action of those drugs that are modified by CYP3A4. CYP3A4 is a member of the cytochrome P450 family of oxidizing enzymes. Several other members of this family are also involved in drug metabolism, but CYP3A4

3285-584: The expression of anti-inflammatory proteins in the nucleus (a process known as transactivation ) and represses the expression of pro-inflammatory proteins in the cytosol by preventing the translocation of other transcription factors from the cytosol into the nucleus ( transrepression ). Glucocorticoids are distinguished from mineralocorticoids and sex steroids by their specific receptors , target cells , and effects. In technical terms, " corticosteroid " refers to both glucocorticoids and mineralocorticoids (as both are mimics of hormones produced by

3358-535: The fasted state, cortisol stimulates several processes that collectively serve to increase and maintain normal concentrations of glucose in the blood. Metabolic effects: Excessive glucocorticoid levels resulting from administration as a drug or hyperadrenocorticism have effects on many systems. Some examples include inhibition of bone formation, suppression of calcium absorption (both of which can lead to osteoporosis ), delayed wound healing, muscle weakness, and increased risk of infection. These observations suggest

3431-490: The following substances. Click on genes, proteins and metabolites below to link to respective articles. This article incorporates text from the United States National Library of Medicine , which is in the public domain . Enzyme Commission number EC numbers do not specify enzymes but enzyme-catalyzed reactions. If different enzymes (for instance from different organisms) catalyze

3504-423: The formation of flashbulb memories of events associated with strong emotions, both positive and negative. This has been confirmed in studies, whereby blockade of either glucocorticoids or noradrenaline activity impaired the recall of emotionally relevant information. Additional sources have shown subjects whose fear learning was accompanied by high cortisol levels had better consolidation of this memory (this effect

3577-409: The fourth month of life and 72% at 12 months. Although CYP3A4 is predominantly found in the liver, it is also present in other organs and tissues of the body, where it may play an important role in metabolism. CP3A4 is the major CYP enzyme in the intestine. CYP3A4 in the intestine plays an important role in the metabolism of certain drugs. Often this allows prodrugs to be activated and absorbed, as in

3650-426: The function and/or numbers of neutrophils , lymphocytes (including both B cells and T cells ), monocytes , macrophages , and the anatomical barrier function of the skin. This suppression, if large enough, can cause manifestations of immunodeficiency , including T cell deficiency , humoral immune deficiency and neutropenia . In addition to the effects listed above, use of high-dose glucocorticoids for only

3723-704: The function of other transcription factors. This latter mechanism appears to be the most likely way that activated glucocorticoid receptor interferes with NF-κB - namely by recruiting histone deacetylase , which deacetylate the DNA in the promoter region leading to closing of the chromatin structure where NF-κB needs to bind. Activated glucocorticoid receptor has effects that have been experimentally shown to be independent of any effects on transcription and can only be due to direct binding of activated glucocorticoid receptor with other proteins or with mRNA. For example, Src kinase which binds to inactive glucocorticoid receptor,

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3796-476: The greatest effects when juice is taken an hour previous to administration of the drug. In addition to grapefruit, other fruits have similar effects. Noni ( Morinda citrifolia ), for example, is a dietary supplement typically consumed as a juice and also inhibits CYP3A4. Pomegranate juice has shown some inhibition in limited studies, but has not yet demonstrated the effect in humans. While over 28 single nucleotide polymorphisms (SNPs) have been identified in

3869-561: The immune response. Inhibition of this transcription factor, therefore, blunts the capacity of the immune system to mount a response. Glucocorticoids suppress cell-mediated immunity by inhibiting genes that code for the cytokines IL-1 , IL-2 , IL-3 , IL-4 , IL-5 , IL-6 , IL-8 and IFN-γ, the most important of which is IL-2. Smaller cytokine production reduces the T cell proliferation. Glucocorticoids, however, not only reduce T cell proliferation, but also lead to another well known effect - glucocorticoid-induced apoptosis. The effect

3942-406: The innate differences in CYP3A4 activation, investigators can better predict drug metabolism and side effects in human CYP3A4 pathways. Estimates of the turnover rate of human CYP3A4 vary widely. For hepatic CYP3A4, in vivo methods yield estimates of the enzyme half-life mainly in the range of 70 to 140 hours, whereas in vitro methods give estimates from 26 to 79 hours. Turnover of gut CYP3A4

4015-696: The last version published as a printed book, contains 3196 different enzymes. Supplements 1-4 were published 1993–1999. Subsequent supplements have been published electronically, at the website of the Nomenclature Committee of the International Union of Biochemistry and Molecular Biology. In August 2018, the IUBMB modified the system by adding the top-level EC 7 category containing translocases. Glucocorticoid Glucocorticoids (or, less commonly, glucocorticosteroids ) are

4088-417: The letters "EC" followed by four numbers separated by periods. Those numbers represent a progressively finer classification of the enzyme. Preliminary EC numbers exist and have an 'n' as part of the fourth (serial) digit (e.g. EC 3.5.1.n3). For example, the tripeptide aminopeptidases have the code "EC 3.4.11.4", whose components indicate the following groups of enzymes: NB:The enzyme classification number

4161-412: The liver. This effect has been attributed to CYP3A4 regulation by the growth hormone signal transduction pathway. In addition to providing an in vivo model, humanized CYP3A4 mice (hCYP3A4) have been used to further emphasize gender differences in CYP3A4 activity. CYP3A4 activity levels have also been linked to diet and environmental factors, such as duration of exposure to xenobiotic substances. Due to

4234-538: The management of familial hyperaldosteronism type 1 . They are not effective, however, for use in the type 2 condition. Glucocorticoids could be used in the treatment of decompensated heart failure to potentiate renal responsiveness to diuretics, especially in heart failure patients with refractory diuretic resistance with large doses of loop diuretics. Resistance to the therapeutic uses of glucocorticoids can present difficulty; for instance, 25% of cases of severe asthma may be unresponsive to steroids. This may be

4307-764: The median CYP3A4 levels measured from surgically removed liver samples of a random sample of women exceeded CYP3A4 levels in the livers of men by 129%. CYP3A4 mRNA transcripts were found in similar proportions, suggesting a pre-translational mechanism for the up-regulation of CYP3A4 in women. The exact cause of this elevated level of enzyme in women is still under speculation, however studies have elucidated other mechanisms (such as CYP3A5 or CYP3A7 compensation for lowered levels of CYP3A4) that affect drug clearance in both men and women. CYP3A4 substrate activation varies amongst different animal species. Certain ligands activate human PXR, which promotes CYP3A4 transcription, while showing no activation in other species. For instance, mouse PXR

4380-412: The metabolism of endogenous and exogenous compounds. These include hydroxylation , epoxidation of olefins, aromatic oxidation , heteroatom oxidations, N- and O- dealkylation reactions, aldehyde oxidations, dehydrogenation reactions, and aromatase activity. Hydroxylation of an sp C-H bond is one of the ways in which CYP3A4 (and cytochrome P450 oxygenases) affects its ligand. In fact, hydroxylation

4453-421: The most commonly used biomarkers to measure stress. Glucocorticoids have numerous non-stress-related functions as well, and glucocorticoid concentrations can increase in response to pleasure or excitement. Various synthetic glucocorticoids are available; these are widely utilized in general medical practice and numerous specialties , either as replacement therapy in glucocorticoid deficiency or to suppress

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4526-499: The presence of aflatoxin B1, M1, and G1. Indeed, due to the enzyme's large and malleable active site, it is possible for the enzyme to bind multiple ligands at once, leading to potentially detrimental side effects. Induction of CYP3A4 has been shown to vary in humans depending on sex. Evidence shows an increased drug clearance by CYP3A4 in women, even when accounting for differences in body weight. A study by Wolbold et al. (2003) found that

4599-419: The promotion of certain types of cancers (see epoxyeicosatetraenoic acid ). CYP3A4 promotes the growth of various types of human cancer cell lines in culture by producing (±)-14,15-epoxyeicosatrienoic acids, which stimulate these cells to grow. The CYP3A4 enzyme is also reported to have fatty acid monooxgenase activity for metabolizing arachidonic acid to 20-Hydroxyeicosatetraenoic acid (20-HETE). 20-HETE has

4672-417: The protein transcortin (also called corticosteroid-binding globulin), whereas all of them bind albumin . In the liver, they quickly metabolize by conjugation with a sulfate or glucuronic acid , and are secreted in the urine . Glucocorticoid potency, duration of effect, and the overlapping mineralocorticoid potency vary. Cortisol is the standard of comparison for glucocorticoid potency. Hydrocortisone

4745-500: The result of genetic predisposition, ongoing exposure to the cause of the inflammation (such as allergens ), immunological phenomena that bypass glucocorticoids, pharmacokinetic disturbances (incomplete absorption or accelerated excretion or metabolism) and viral and/or bacterial respiratory infections. Glucocorticoid drugs currently being used act nonselectively, so in the long run they may impair many healthy anabolic processes. To prevent this, much research has been focused recently on

4818-404: The results are not consistent for all cell types and conditions; there is no generally accepted, general mechanism for transrepression. New mechanisms are being discovered where transcription is repressed, but the activated glucocorticoid receptor is not interacting with DNA, but rather with another transcription factor directly, thus interfering with it, or with other proteins that interfere with

4891-419: The same reaction, then they receive the same EC number. Furthermore, through convergent evolution , completely different protein folds can catalyze an identical reaction (these are sometimes called non-homologous isofunctional enzymes ) and therefore would be assigned the same EC number. By contrast, UniProt identifiers uniquely specify a protein by its amino acid sequence. Every enzyme code consists of

4964-711: The second-line treatment for asthma . They are also administered as post-transplantory immunosuppressants to prevent the acute transplant rejection and the graft-versus-host disease . Nevertheless, they do not prevent an infection and also inhibit later reparative processes . Newly emerging evidence showed that glucocorticoids could be used in the treatment of heart failure to increase the renal responsiveness to diuretics and natriuretic peptides. Glucocorticoids are historically used for pain relief in inflammatory conditions. However, corticosteroids show limited efficacy in pain relief and potential adverse events for their use in tendinopathies . Any glucocorticoid can be given in

5037-408: The source of stress/emotional arousal. In contrast to the dose-dependent enhancing effects of glucocorticoids on memory consolidation, these stress hormones have been shown to inhibit the retrieval of already stored information. Long-term exposure to glucocorticoid medications, such as asthma and anti-inflammatory medication, has been shown to create deficits in memory and attention both during and, to

5110-859: The substrates tend to have a low K D (between 5–150 μM) and low solubility in aqueous solutions. A successful strategy in isolating the bound enzyme is the functional stabilization of monomeric CYP3A4 on silver nanoparticles produced from nanosphere lithography and analyzed via localized surface plasmon resonance spectroscopy (LSPR). These analyses can be used as a high-sensitivity assay of drug binding, and may become integral in further high-throughput assays utilized in initial drug discovery testing. In addition to LSPR, CYP3A4-Nanodisc complexes have been found helpful in other applications including solid-state NMR , redox potentiometry, and steady-state enzyme kinetics . Following are lists of selected substrates , inducers and inhibitors of CYP3A4. Where classes of agents are listed, there may be exceptions within

5183-570: The two main products of inflammation, prostaglandins and leukotrienes . They inhibit prostaglandin synthesis at the level of phospholipase A2 as well as at the level of cyclooxygenase /PGE isomerase (COX-1 and COX-2), the latter effect being much like that of NSAIDs , thus potentiating the anti-inflammatory effect. In addition, glucocorticoids also suppress cyclooxygenase expression. Glucocorticoids marketed as anti-inflammatories are often topical formulations, such as nasal sprays for rhinitis or inhalers for asthma . These preparations have

5256-457: Was catalyzed were in common use. Most of these names have fallen into disuse, though a few, especially proteolyic enzymes with very low specificity, such as pepsin and papain , are still used, as rational classification on the basis of specificity has been very difficult. By the 1950s the chaos was becoming intolerable, and after Hoffman-Ostenhof and Dixon and Webb had proposed somewhat similar schemes for classifying enzyme-catalyzed reactions,

5329-486: Was more important in men). The effect that glucocorticoids have on memory may be due to damage specifically to the CA1 area of the hippocampal formation. In multiple animal studies, prolonged stress (causing prolonged increases in glucocorticoid levels) have shown destruction of the neurons in the hippocampus area of the brain, which has been connected to lower memory performance. Glucocorticoids have also been shown to have

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