Pii: s0006-2952(02)01121-8

Biochemical Pharmacology 64 (2002) 355±361 Department of Molecular and Cellular Biology, Ligand Pharmaceuticals, 10275 Science Center Drive, San Diego, CA 92121, USA Glucocorticoids are the most effective anti-in¯ammatory agents known. However,the use of these powerful molecules is plagued by a host of serious,sometimes life-threatening side-effects. The search for new compounds that maintain the ef®cacy of the steroids without some of the side-effects has entered a new phase. New approaches are leading to novel kinds of steroidal and non-steroidal compounds with unique pro®les that may represent the next generation of safer glucocorticoids.
# 2002 Elsevier Science Inc. All rights reserved.
Keywords: Selective glucocorticoid receptor modulators; Steroid receptor ligand; Non-steroidal anti-in¯ammatory agent nately,early on,it was discovered that these compounds had a severely negative impact on patients to whom they Early efforts to understand endocrine function focused were administered. Efforts from that point on have focused on extracts derived from glands whose removal caused on ®nding molecules that have anti-in¯ammatory ef®cacy speci®c systemic pathologies in animals. The adrenal was equal to that of the steroids,but with a reduction in side- one such gland. Organic extracts from this gland could be effects. Progress has been made with several synthetic used to ameliorate the symptoms of Addison's disease steroidal versions that exhibit increased receptor speci®- (later discovered to be caused by the speci®c lack of the city and potency (dexamethasone) as well as versions for glucocorticoid hormone cortisol). Addison's patients exhi- use in topical,inhaled,or other non-oral formulations.
bit hyperpigmentation of the skin,hypoglycemia,and salt These,typically,are extremely potent steroids with high craving,among other symptoms. These patients do not ef®cacy that are cleared rapidly by ®rst-pass metabolism.
respond effectively to stress,creating the potential for an This pro®le results in excellent ef®cacy at the point of Addisonian crisis,a disease cascade that is potentially life- application (e.g. lung and skin) but with reduced,although threatening. The majority of these symptoms can be elimi- nated with the injection of adrenal extracts.
The isolation of the active components from this gland by Tadeus Reichstein and Edward Kendall,and the sub- sequent use in patients with rheumatoid arthritis by Philip Hench,garnered all three the Nobel Prize in 1950. These Corticosteroids produced in the adrenal gland undergo agents were remarkably effective at inhibiting many forms metabolism into two compounds (glucocorticoids and of in¯ammation and were used at high doses over long mineralocorticoids) with markedly different activities; periods of time,resulting in excellent ef®cacy. Unfortu- glucocorticoids like cortisol have effects on carbohydrate, fat,and protein metabolism,and mineralocorticoids like aldosterone have effects on sodium levels by raising Tel.: ‡1-858-550-7807; fax: ‡1-858-550-7235.
reabsorption in the kidney The responses to these E-mail address: jminer@ligand.com (J.N. Miner).
Abbreviations: CRH,corticotropin-releasing hormone; CRF,corticotro- hormones are mediated by two different intracellular pin-releasing factor; ACTH,adrenocorticotropin hormone; HPA,hypotha- receptors,which are capable of binding to and thereby lamic-pituitary-adrenal; GVHD,graft-versus-host disease; PEPCK, being activated by these steroids,translocating to the phosphoenol pyruvate carboxy kinase; LBD,ligand-binding domain; nucleus,and regulating speci®c target genes. This signal GRIP-1,GR interacting protein 1; NFkB,nuclear factor-kappa B; AP-1, activator protein 1; PPAR,peroxisome proliferator activated receptor; PGC- transduction pathway is unique in that it utilizes a single 1,PPARg coactivator 1; HNF-4,hepatocyte nuclear factor 4.
protein that is both the proximal ligand receptor as well as 0006-2952/02/$ ± see front matter # 2002 Elsevier Science Inc. All rights reserved.
PII: S 0 0 0 6 - 2 9 5 2 ( 0 2 ) 0 1 1 2 1 - 8 J.N. Miner / Biochemical Pharmacology 64 (2002) 355±361 the transcription factor that interacts with DNA in the patients present with a combination of symptoms grouped nucleus. The GR,in particular,is responsible for up- under the heading `Cushing's syndrome' The symp- regulating and down-regulating a wide range of genes toms include central obesity,glucose intolerance,myopa- affecting a number of critical metabolic pathways. Glu- thy,and hypertension,among others. The pathophysiology cocorticoids are commonly known as the stress hormones, of this condition is most often related to dysregulation of and,under normal circumstances,they are crucial to the the system that produces glucocorticoids due to tumors or ability of the body to respond and adapt to stress. Stress other endocrine problems. Certain adrenal tumors are causes signaling within the two key components of the known to secrete large quantities of cortisol and are not stress response,CRH neurons found in the paraventricular regulated by normal feedback mechanisms. Over-secretion nucleus of the hypothalamus and in other areas of the of signaling molecules within the glucocorticoid produc- central nervous system as well as the noradrenergic neu- tion pathway,CRF or ACTH by the pituitary or non- rons of the locus-ceruleus-norepinephrine system. Activa- pituitary cells,can also increase serum levels of cortisol tion of these systems induces psychological,behavioral, and physical changes that provide an adaptive bene®t in the The last and perhaps the most common way in which short term. The HPA axis is on the receiving end of signals imbalances in the stress response system can present from the CRH neurons. This axis is the primary regulator themselves is when patients are administered exogenous of endogenous glucocorticoid production. CRF from CRH neurons acts on the anterior pituitary gland to cause the Glucocorticoids are extremely effective and frequently secretion of ACTH,which,in turn,induces corticosteroid used therapeutic agents that are administered for a wide production and release from the adrenal gland. Thus,in range of disorders. Supplemental glucocorticoids can response to stress,the HPA axis is activated,and gluco- replace cortisol absent in various adrenal insuf®ciency corticoid levels in serum increase. The behavioral and syndromes These compounds are also effective psychological changes that occur when cortisol levels rise anti-in¯ammatory agents for many autoimmune and are indicative of a ®ght or ¯ight response and include in¯ammatory disorders,such as rheumatoid arthritis and increases in alertness,mental acuity,pain tolerance,tem- asthma. With rheumatoid arthritis,treatment with non- perature,and euphoria coupled with decreases in sexual steroidal anti-in¯ammatory drugs (NSAIDs) provides sig- desire,reproductive behavior,and appetite The phy- ni®cant bene®t; however,the progression of the disease sical/physiological changes include increases in respiration eventually demands the use of glucocorticoids. Steroids rate,oxygenation,cardiovascular tone,blood ¯ow,pres- inhibit the signs and symptoms of the in¯ammation asso- sure,and heart rate. Accompanying these are adjustments ciated with rheumatoid arthritis,but fail to reverse any in metabolism to provide glucose and energy by increasing structural damage that has already occurred in the joint.
gluconeogenesis in the liver and lipolysis in fat depots.
Additionally,patients with asthma often use inhaled and Protein is broken down to provide substrates for gluconeo- oral steroids to control exacerbation of their condition.
genesis. A number of peripheral systems unnecessary to the Immunosuppressive therapy for transplant rejection and short-term stress response are inhibited. These suppressed autoimmune disorders often makes use of short-term,high- functions include growth,reproduction,food absorption, dose treatment with steroids followed by more protracted and the immune response. Interestingly,the stress response lower dose treatment to reduce the cell-mediated response also provides an autoregulatory mechanism to reduce the to transplanted foreign tissue. Patients receiving bone production of glucocorticoid after high levels have been marrow transplants occasionally develop acute GVHD.
achieved. This is accomplished by feedback of glucocorti- Glucocorticoids are extremely useful in GVHD; other coids onto the signaling pathways that induce glucocorti- therapeutics are used only for steroid-resistant GVHD coid production. Glucocorticoids inhibit the expression of genes involved in activating the HPA axis,including multiple myeloma and certain lymphomas and leukemias, corticotropin-releasing factor and ACTH,thereby regulat- respond well to combination therapies that include the ing corticosteroid production from the adrenal gland glucocorticoids prednisone or dexamethasone.
There are several situations when this carefully balanced Exposure to high,sustained levels of corticosteroids by system can go awry. Chronic,uncontrolled stress leads to any mechanism uncouples the normal metabolic processes long-term activation of the HPA axis and sustained,high from autoregulatory feedback mechanisms and induces a glucocorticoid levels. Pathological conditions in which stress response physiological state that cannot be main- activation of the HPA axis has been demonstrated include tained long term without severe consequences. The numer- depression,obsessiveÐcompulsive disorder,alcohol and ous side-effects experienced by patients administered drug abuse,and anorexia nervosa The action of steroids over the long term are perhaps the clearest exam- glucocorticoids in response to chronic stress is decidedly ple of this. The response to glucocorticoids is complex,due in large measure to the wide variety of physiological Imbalances in cortisol production can also occur in contexts in which glucocorticoids act . Complications certain conditions that overproduce glucocorticoids. These are time- and dose-dependent and can occur acutely with J.N. Miner / Biochemical Pharmacology 64 (2002) 355±361 very high doses,or more slowly with chronic exposure and the glucose production pathways. While bene®cial in the lower doses. Fortunately,glucocorticoid-regulated clinical short term,this decreases overall muscle function when markers of speci®c side-effects are available from the activated for an extended period of time.
extensive clinical trials conducted over the years with The behavioral effects of glucocorticoids are of great glucocorticoids. These markers are relevant to many of concern to patients. Glucocorticoids have long been known the impacts of glucocorticoids on bone,fat,and carbohy- to have psychogenic effects in a subset of patients when drate metabolism. Most are readily monitored in response given at high doses. Approximately 5% of patients will to short-term exposure to glucocorticoids and include experience some degree of inappropriate euphoria,psy- serum cortisol,a measure of HPA suppression,lipid pro®le chosis,or depression Patients are also quite con- changes,which measure weight effects,serum glucose and cerned with the effects of glucocorticoids on fat insulin levels,a measure of effects on insulin resistance redistribution and weight gain. Fat and muscle are lost and hepatic glucose output,and urinary collagen peptides from limbs,but truncal and visceral areas actually accu- and serum osteocalcin that help assess the impact of mulate fat. Facial,supraclavical,and posterior cervical fat compounds on bone metabolism. Together,these markers depots are particularly sensitive to glucocorticoids,result- can assist in the assessment of speci®c compounds early in ing in the moon face and buffalo hump characteristic of clinical trials. The speci®c side-effects of glucocorticoids long-term glucocorticoid treatment Even one dose of can be ranked by patients and physicians. These vary a glucocorticoid is suf®cient to increase hepatic glucose somewhat depending on the person doing the ranking.
production and increase insulin resistance of peripheral In particular,patients tend to highlight the physical and tissues. The glucocorticoid effect on glycemic control is mental changes that accompany long-term steroid use.
thought to target insulin signaling . Glucocorticoids These include fat redistribution and weight gain and affect insulin-mediated increases in blood ¯ow to muscles steroid-induced psychosis/neurosis. Physicians,on the They decrease key insulin receptor signaling mole- other hand,tend to concentrate on problems that affect cules and increase glucose output by increasing the rate- patient medical care,which include hyperglycemia,gen- limiting enzyme in gluconeogenesis,PEPCK .
eralized insulin resistance,as well as suppression of the Glucocorticoids also inhibit the release of insulin from HPA axis. However,without question,the single most the pancreas,acting directly on the pancreatic b cells. This important side-effect from the standpoint of many physi- action may involve apoptosis of b cell populations,leading cians is osteoporosis. This side-effect alone accounts for an to decreased insulin production as well as more direct enormous amount of morbidity among patients receiving inhibition of insulin expression The molecular glucocorticoids. Long-term glucocorticoid treatment often details underpinning regulation of hepatic glucose produc- results in some degree of osteoporosis in patients. Because tion have been made clearer recently by discoveries linking these patients also suffer from decreased muscle mass as a GR,other transcription factors,and cyclic AMP (cAMP) in consequence of steroid treatment,they are more suscep- tible to falling. The consequences of falls and subsequent fractures become enormous when one considers that many of these patients are already sick with a debilitating dis- ease. A hip fracture late in life with its attendant inactivity and increased potential for pneumonia can have fatal The GR acts as a ligand-regulated transcription factor consequences for elderly patients. Susceptibility to frac- responding to circulating cortisol. It is a member of the tures and aseptic necrosis of the femoral head increases large family of intracellular receptors comprised of both within months of starting glucocorticoid therapy the nuclear hormone receptors as well as the steroid Steroids degrade the quality of trabecular bone,resulting in receptor subfamilies. The protein itself is composed of an increase in fracture rate . Bone loss is highest in the three general domains: a DNA-binding domain,a C-term- ®rst 6 months of therapy,after which patients continue to inal ligand-binding domain (LBD),and an N-terminal lose bone,but at a slower rate. When taken off steroids, activation domain. It is capable of regulating transcription patients do appear to partially regain bone The loss both negatively and positively and is localized to the of muscle compounds the osteoporosis problem. Gluco- cytoplasm in the absence of hormone. The receptor is held corticoid-induced myopathy results in decreased strength in an inactive state poised to bind ligand by interaction with and muscle mass. The mechanism by which glucocorti- a chaperonin complex comprised of heat shock proteins.
coids affect muscle mass is partially due to hypogonadism Upon binding ligand,the receptor undergoes a conforma- observed in many patients with the consequent decline in tional change that dissociates the heat shock proteins and levels of the sex steroids estrogen and testosterone,which activates a number of receptor functions including DNA are responsible for contributing to the maintenance of both binding activity,nuclear localization,and transcriptional muscle and bone mass Furthermore,mimicking a regulation. The latter involves the direct and indirect inter- stress response,muscle is broken down and utilized as a action with a large number of transcription factors critical source of substrates and energy for the increased activity in to gene regulation including RNA polymerase as well J.N. Miner / Biochemical Pharmacology 64 (2002) 355±361 as various polymerase-associated proteins. The complex repression prompted a recent analysis of the collage- that forms at a regulated gene is quite large,and the nase-3 gene promoter under glucocorticoid-repressed con- receptor likely does not contact RNA polymerase directly, ditions Given the previously described role for GRIP-1 but instead utilizes several types of so-called ``coactivator'' as a coactivator,it came as a surprise when these authors proteins to bridge the gap between itself and the polymer- demonstrated an important role for GRIP-1 in repression.
ase The details of the interaction between the receptor They demonstrated that GRIP was recruited to the col- and these coactivators are understood from genetic,bio- lagenase promoter during the act of repression by the GR.
chemical,and crystallographic standpoints for only a few The ligand-dependent recruitment of these proteins might speci®c receptorÐcoactivator pairs. In general,these inter- be used as a readout to detect potentially bene®cial ther- actions make use of the LBD of the receptor,although other less well-characterized interactions clearly occur in The search for a novel glucocorticoid that has the anti- the N-terminal and DNA binding domains Coactiva- in¯ammatory properties of conventional steroids without tors bind to the LBD of the GR in a hormone-dependent one or more of the side-effects has been a long-standing fashion,interacting directly with the extreme C-terminal goal of the ®eld. Much effort has been spent on modifying portion of the LBD. This interaction domain is formed by the steroid backbone to achieve this sort of increased the juxtaposition of several helical segments within the therapeutic index; however,these efforts have met with protein. The interaction surface between these transcrip- little success. De¯azacort,a D-ring-substituted steroid tion factors is comprised of a hydrophobic pocket on the otherwise similar to cortisol,was touted originally as a receptor and a helical sequence containing an LxxLL powerful anti-in¯ammatory molecule exhibiting more amino acid motif on the coactivator This interaction selective,i.e. reduced,activity,in particular on bone and is very sensitive to the structure of the ligand bound in the on glucose metabolism. Initially,clinical data supported pocket. Coactivators typically bind avidly in the presence this notion . However,subsequent trials that adjusted of agonists,but fail to bind in the presence of antagonist the steroid dose to maintain equivalent anti-in¯ammatory ligands. In fact,this is likely the mechanism of antagonist ef®cacy usually needed higher levels of de¯azacort. Unfor- action. This conformational sensitivity is due to the tunately,at these higher doses,the advantages of de¯azacort changes in receptor structure brought about by the structure disappeared The ®eld was re-energized by the dis- of the ligand bound in the pocket. The receptor appears to covery of the likely mechanism of GR-mediated repression actually condense around the ligand during the binding of a wide variety of pro-in¯ammatory genes. The receptor reaction,meaning that structural changes in the ligand are was shown to bind directly to speci®c transcription factors transmitted directly to the receptor and to the receptor (NFkB and AP-1) involved in up-regulating in¯ammatory surfaces that interact with coactivators Thus,ligands genes. This represented a unique mechanism that was can change the ability of the receptor to bind to coactivators.
genetically separable from transcriptional activation. The These coactivators may also play a role in the tissue-speci®c search began for ligands that could induce transcriptional activity of glucocorticoids. Although many coactivators are repression,but hinder transcriptional activation. In 1997, expressed widely,some have been described that exhibit a the ®rst compounds that separated transactivation from restricted tissue expression pattern Coactivators are not only involved in transcriptional activation,but they also These compounds were steroidal in nature,were very appear to play a role in transcriptional repression. Recent ef®cient inhibitors of both AP-1- and NFkB-mediated gene data have demonstrated that transcriptional repression by induction,and were strong anti-in¯ammatory agents in many members of the nuclear hormone receptor family is vivo. They also were reported to have reduced ability to dependent upon speci®c corepressor proteins that bind activate gene expression in some,but not all cellular directly to the receptor in the absence of hormone and contexts. Unfortunately,thus far,no in vivo therapeutic inhibit the transcription process by recruiting histone dea- advantage has been demonstrated for these types of mole- cetylases ,which appear to condense chromatin and cules when side-effects were measured This result therefore repress transcription . However,most mem- calls into question the usefulness of the activation±repres- bers of the steroid receptor subfamily are sequestered in the cytoplasm in the absence of hormone and exhibit gene- We have also pursued this hypothesis as an approach to speci®c repression or activation only when hormone is discovering selective GR modulators. An example of the present. Corepressors have not yet been shown to bind compounds identi®ed during this collaborative effort steroid receptors during normal gene regulation between Ligand Pharmaceuticals and Abbott Laboratories although there is evidence for interaction when bound to is AL-438 (Abbott-Ligand 438),which was shown to be a speci®c,non-steroidal ligand for the GR that exhibited a The ubiquitous coactivator GRIP-1 has been shown to unique pro®le,both in vitro and in vivo. The molecule is bind to GR and other intracellular receptors and to enhance fully ef®cacious at transcriptional repression compared their transcriptional activation activity . Unresolved with prednisolone on certain genes related to the anti- questions regarding the mechanism of steroid receptor in¯ammatory aspects of glucocorticoid activity (E-selectin J.N. Miner / Biochemical Pharmacology 64 (2002) 355±361 and interleukin-6),but is weaker (a partial agonist) for This is consistent with the gene-speci®c activity transcriptional activation. Using other promoters in differ- described earlier. The mechanism may be found in the ent cell backgrounds,AL-438 is more active as a transcrip- fact that AL-438 generates a receptor conformation that tional activator. Thus,AL-438 does not completely differs from steroids,which in turn changes the spectrum of separate transcriptional repression from activation,but coactivators with which the receptor can interact. Certain instead appears to be separating activities in a gene-speci®c coactivators bind GR with identical af®nity in the presence fashion. In animal models,AL-438 was as ef®cacious as of either AL-438 or prednisolone,while others exhibit prednisolone at inhibiting in¯ammation. Importantly,AL- signi®cantly reduced af®nity in the presence of this com- 438 exhibited signi®cantly reduced impact on fasting pound. We believe that since different genes have different glucose levels compared with prednisolone,suggesting requirements for speci®c coactivators,this may be the that this compound might not cause the diabetogenic molecular rationale for AL-438's gene-selective pro®le.
effects of steroidal glucocorticoids.
The coactivator GRIP-1 is an example of a potential An as-yet-unanswered question is whether the improved mediator of gene-speci®c effects,given its demonstrated pro®le of AL-438 in vivo is a direct result of its altered effect involvement in both transcriptional repression and activa- on GR structure and function as detected by in vitro assays.
tion. We have examined the interactions between GRIP-1 It is possible that it is the speci®c conformation of the and GR in a variety of mammalian two-hybrid and GST receptor detected by our in vitro assays that is responsible pull-down assays. Our ®ndings indicate that,in a manner for the therapeutically bene®cial pro®le observed in rodents.
similar to prednisolone,AL-438 will induce the interaction Fig. 1. Selective glucocorticoid receptor modulator (SGRM) coactivator hypothesis. This figure depicts a model that attempts to distinguish the effects of steroidal glucocorticoids from SGRMs. Both compounds are fully efficacious at binding GR and causing the interaction with GRIP-1,a coactivator involved in repression of inflammatory genes by GR. The model suggests that this interaction is,in part,responsible for the anti-inflammatory activity of both compounds. Of course this is likely not the entire explanation. That said,when examining the ability of steroids and SGRMs to induce the interaction with PGC-1,a coactivator involved in glucose homeostasis in the liver among other things,a strikingly different result is found. The SGRM is weaker at inducing the PGC-1 interaction than the steroid. This may help explain the reduced negative impact on glucose metabolism from the SGRM. Thus,the reduced PGC-1 interaction may translate into reduced side-effects in liver and possibly other tissues as well.
J.N. Miner / Biochemical Pharmacology 64 (2002) 355±361 between GRIP and GR ef®ciently. This ®nding suggests exhibitactivitiesthathavethepromiseofleadingtopowerful, that the differences between AL-438 and steroids in vivo yet safer GR-dependent anti-in¯ammatory agents.
are not to be explained by the GRIP-1ÐGR interaction, with the caveat that we have not tested all cell contexts with this approach. Another example of potential coactivators for the GR is the PGC-1,originally characterized as a PPAR coactivator highly expressed in brown fat,involved [1] Rohatagi S,Rhodes GR,Chaikin P. Absolute oral versus inhaled in fat differentiation ,and more recently shown to play bioavailability: significance for inhaled drugs with special reference to inhaled glucocorticoids. J Clin Pharmacol 1999;39:661±3.
a critical role in glucocorticoid-mediated stimulation of [2] Mackie AE,Bye A. The relationship between systemic exposure to glucose production from the liver. The PEPCK gene fluticasone propionate and cortisol reduction in healthy male volun- requires the action of PGC-1 together with the transcription teers. Clin Pharmacokinet 2000;39:47±54.
factor HNF-4 to ef®ciently respond to glucocorticoids [3] Orth DN,Kovacs WJ. The adrenal cortex. In: Wilson JD,Foster DW, These authors demonstrate that PGC-1 binds Kronenberg HM,Larsen PR,editors. Williams textbook of endocri- nology. Philadelphia: Saunders,1998. p. 517.
directly to GR and to HNF-4 and is critical for the appro- [4] Peeke PM,Chrousos GP. Hypercortisolism and obesity. Ann NYAcad priate response to both cAMP signaling and glucocorti- coids. We became interested in this protein initially [5] Chrousos GP. The role of stress and the hypothalamic-pituitary- because of the critical role played by PGC-1 in fat meta- adrenal axis in the pathogenesis of the metabolic syndrome: neuro- bolism and differentiation activity intimately tied endocrine and target tissue-related causes. Int J Obes Relat Metab to the effects of glucocorticoids. The PGC-1ÐGR con- [6] Gold PW,Gwirtsman H,Avgerinos PC,Nieman LK,Gallucci WT, nection was strengthened considerably by the demonstra- Kaye W,Jimerson D,Ebert M,Rittmaster R,Loriaux DL. Abnormal tion of direct binding to GR and most recently by its hypothalamic-pituitary-adrenal function in anorexia nervosa. Patho- involvement in glucocorticoid effects on glucose produc- physiologic mechanisms in underweight and weight-corrected pa- tion . Thus,we hypothesized that the reduced tients. N Engl J Med 1986;314:1335±42.
[7] Gold PW,Goodwin FK,Chrousos GP. Clinical and biochemical impact of AL-438 on fat metabolism and glucose levels manifestations of depression. Relation to the neurobiology of stress compared with prednisolone might be connected to (First of two parts). N Engl J Med 1988;319:348±53.
changes in the interaction with PGC-1. This notion was [8] Norton JA,Li M,Gillary J,Le HN. Cushing's syndrome. Curr Probl tested with direct interaction assays that demonstrated that PGC-1 could bind directly to the GR in response to [9] Boumpas DT,Chrousos GP,Wilder RL,Cupps TR,Balow JE.
Glucocorticoid therapy for immune-mediated diseases: basic and prednisolone and dexamethasone. The response to AL- clinical correlates. Ann Intern Med 1993;119:1198±208.
438 in the same assays was reduced,suggesting that,in [10] Deeg HJ,Henslee-Downey PJ. Management of acute graft-versus-host contrast to GRIP-1,AL-438 did not induce a GR con- disease. Bone Marrow Transplant 1990;6:1±8.
formation that ef®ciently interacted with PGC-1. [11] Schleimer RP,Freeland HS,Peters SP,Brown KE,Derse CP. An outlines the hypothesis that these data supported.
assessment of the effects of glucocorticoids on degranulation,che- This idea suggested that for the inhibition of in¯amma- motaxis,binding to vascular endothelium and formation of leukotriene tory mediators (collagenase,interleukin-6,and E-selectin), 4 by purified human neutrophils. J Pharmacol Exp Ther 1989;250: interaction with GRIP-1 was important d both AL- [12] Axelrod J,Reisine TD. Stress hormones: their interaction and regula- 438 and steroids induce this interaction ef®ciently. In contrast,the interaction with PGC-1 is known to be [13] Lane NE,Lukert B. The science and therapy of glucocorticoid- important for the effects of glucocorticoids on liver glucose induced bone loss. Endocrinol Metab Clin North Am 1998;27:465±83.
[14] Ralston SH. The genetics of osteoporosis. Bone 1999;25:85±6.
production and hyperglycemia AL-438 is less [15] van Staa TP,Leufkens HGM,Abenhaim L,Zhang B,Cooper C. Oral ef®cient at inducing PGC-1 interactions when compared corticosteroids and fracture risk: relationship to daily and cumulative with steroids,perhaps explaining the differences between doses. Rheumatology (Oxford) 2000;39:1383±9.
the compound and the steroids on glucose levels in vivo.
[16] Crilly R,Cawood M,Marshall DH,Nordin BE. Hormonal status in This hypothesis remains to be tested by directly demon- normal,osteoporotic and corticosteroid-treated postmenopausal wo- strating the involvement of PGC-1 and GRIP-1 in the [17] Doerr P,Pirke KM. Cortisol-induced suppression of plasma testoster- differential activity of AL-438. Furthermore,the differen- one in normal adult males. J Clin Endocrinol Metab 1976;43:622±9.
tial interactions induced by these compounds may extend [18] The Boston Collaborative Drug Surveillance Program. Acute adverse reactions to prednisone in relation to dosage. Clin Pharmacol Ther For the past 30 years,efforts to develop new,more power- [19] Baxter JD. The effects of glucocorticoid therapy. Hosp Pract (Off Ed) ful,and safer anti-in¯ammatory agents that work through the GR have concentrated mainly on the steroid backbone.
[20] Tappy L,Randin D,Vollenweider P,Vollenweider L,Paquot N, Recent discoveries of the molecular and cellular aspects of Scherrer U,Schneiter P,Nicod P,Jequier E. Mechanisms of dexa- GR activity have opened several exciting new approaches to methasone-induced insulin resistance in healthy humans. J Clin En- this effort. Indeed,recent advances in chemistry and screen- [21] Laakso M,Edelman SV,Brechtel G,Baron AD. Decreased effect of ing,together with new molecular approaches,have allowed insulin to stimulate skeletal muscle blood flow in obese man. A novel the identi®cation of novel non-steroidal compounds that mechanism for insulin resistance. J Clin Invest 1990;85:1844±52.
J.N. Miner / Biochemical Pharmacology 64 (2002) 355±361 [22] Sutherland C,O'Brien RM,Granner DK. New connections in the [34] Wagner BL,Norris JD,Knotts TA,Weigel NL,McDonnell DP. The regulation of PEPCK gene expression by insulin. Philos Trans R Soc nuclear corepressors NCoR and SMRT are key regulators of both ligand- and 8-bromo-cyclic AMP-dependent transcriptional activity of [23] Granner DK,Sasaki K,Chu D. Multihormonal regulation of phos- the human progesterone receptor. Mol Cell Biol 1998;18:1369±78.
phoenolpyruvate carboxykinase gene transcription. The dominant role [35] Hong H,Kohli K,Trivedi A,Johnson DL,Stallcup MR. GRIP-1,a of insulin. Ann NY Acad Sci 1986;478:175±90.
novel mouse protein that serves as a transcriptional coactivator in yeast [24] Fernandez-Mejia C,Medina-Martinez O,Martinez-Perez L,Goodman for the hormone binding domains of steroid receptors. Proc Natl Acad PA. The human insulin gene contains multiple transcriptional ele- ments that respond to glucocorticoids. Pancreas 1999;18:336±41.
[36] Rogatsky I,Zarember KA,Yamamoto KR. Factor recruitment and [25] Delaunay F,Khan A,Cintra A,Davani B,Ling Z-C,Andersson A, TIF2/GRIP-1 corepressor activity at a collagenase-3 response element OÈstenson C-G,Gustafsson J-AÊ,Efendic S,Okret S. Pancreatic b cells that mediates regulation by phorbol esters and hormones. EMBO J are important targets for the diabetogenic effects of glucocorticoids. J [37] Markham A,Bryson HM. Deflazacort. A review of its pharmacolo- [26] Lambillotte C,Gilon P,Henquin J-C. Direct glucocorticoid inhibition gical properties therapeutic efficacy. Drugs 1995;50:317±33.
of insulin secretion. An in vitro study of dexamethasone effects in [38] Canalis E,Avioli L. Effects of deflazacort on aspects of bone forma- mouse islets. J Clin Invest 1997;99:414±23.
tion in cultures of intact calvariae and osteoblast-enriched cells. J Bone [27] Jenkins BD,Pullen CB,Darimont BD. Novel glucocorticoid receptor coactivator effector mechanisms. Trends Endocrinol Metab [39] VayssieÁre BM,Dupont S,Choquart A,Petit F,Garcia T,Marchandeau C,Gronemeyer H,Resche-Rigon M. Synthetic glucocorticoids that [28] Westin S,Rosenfeld MG,Glass CK. Nuclear receptor coactivators.
dissociate transactivation and AP-1 transrepression exhibit anti-in- flammatory activity in vivo. Mol Endocrinol 1997;11:1245±55.
[29] Knutti D,Kralli A. PGC-1,a versatile coactivator. Trends Endocrinol [40] Belvisi MG,Brown TJ,Wicks S,Foster ML. New glucocorticosteroids with an improved therapeutic ratio? Pulm Pharmacol Ther 2001;14: [30] Spiegelman BM,Puigserver P,Wu Z. Regulation of adipogenesis and energy balance by PPARg and PGC-1. Int J Obes Relat Metab Disord [41] Belvisi MG,Wicks SL,Battram CH,Bottoms SEW,Redford JE, Woodman P,Brown TJ,Webber SE,Foster ML. Therapeutic benefit of [31] Heinzel T,Lavinsky RM,Mullen T-M,SoÈderstroÈm M,Laherty CD, a dissociated glucocorticoid and the relevance of in vitro separation of Torchia J,Yang W-M,Brard G,Ngo SD,Davie JR,Seto E,Eisenman RN,Rose DW,Glass CK,Rosenfeld MG. A complex containing N- CoR,mSin3 and histone deacetylase mediates transcriptional repres- [42] Herzig S,Long F,Jhala US,Hedrick S,Quinn R,Bauer A,Rudolph D, Schutz G,Yoon C,Puigserver P,Spiegelman B,Montminy M. CREB [32] Dressel U,Thormeyer D,Altincicek B,Paululat A,Eggert M, regulates hepatic gluconeogenesis through the coactivator PGC-1.
Schneider S,Tenbaum SP,Renkawitz R,Baniahmad A. Alien,a highly conserved protein with characteristics of a corepressor for [43] Yoon JC,Puigserver P,Chen G,Donovan J,Wu Z,Rhee J,Adelmant members of the nuclear hormone receptor superfamily. Mol Cell Biol G,Stafford J,Kahn CR,Granner DK,Newgard CB,Spiegelman BM.
Control of hepatic gluconeogenesis through the transcriptional coac- [33] Horlein AJ,Naar AM,Heinzel T,Torchia J,Gloss B,Kurokawa R, tivator PGC-1. Nature 2001;413:131±8.
Ryan A,Kamei Y,Soderstrom M,Glass CK. Ligand-independent [44] Knutti D,Kaul A,Kralli A. A tissue-specific coactivator of steroid repression by the thyroid hormone receptor mediated by a nuclear receptors,identified in a functional genetic screen. Mol Cell Biol receptor co-repressor. Nature 1995;377:397±404.

Source: http://curriculum.hsc.usc.edu/md_phd_journal/Biochemical%20Pharmacology%20-%20Miner.pdf

Resume

Publikationsverzeichnis Prof. Dr. med. Anita Rauch A) Originalarbeiten 108. Göhring I, Tagariello A, Endele S, Stolt CC, Ghassibé M, Fisher M, Thiel CT, Trautmann U, Vikkula M, Winterpacht A, FitzPatrick DR, Rauch A (2009) Disruption of ST5 is associated with mental-retardation and multiple congenital anomalies. J Med Genet, in press 107. Segel R, Levy-Lahad E, Pasutto F, Picard

File://v:\creative%20services\mem\mem5323\html%20build\pdf\mem5

Newsletter Sections: Message from the President - Charles Bouloux Market Highlight - Marine / E-Marine The month of May was a time of focus and direction for our regional AIG Events in the Region Regional Management conference in Oman. The conference enforced our focus and direction on servicing our MEMSA Newsroom customer und

Copyright © 2018 Predicting Disease Pdf