Corticosteroid receptor hypothesis

Corticosteroids have been used as drug treatment for some time. Lewis Sarett of Merck & Co. was the first to synthesize cortisone, using a complicated 36-step process that started with deoxycholic acid, which was extracted from ox bile . [43] The low efficiency of converting deoxycholic acid into cortisone led to a cost of US $200 per gram. Russell Marker , at Syntex , discovered a much cheaper and more convenient starting material, diosgenin from wild Mexican yams . His conversion of diosgenin into progesterone by a four-step process now known as Marker degradation was an important step in mass production of all steroidal hormones, including cortisone and chemicals used in hormonal contraception . [44] In 1952, . Peterson and . Murray of Upjohn developed a process that used Rhizopus mold to oxidize progesterone into a compound that was readily converted to cortisone. [45] The ability to cheaply synthesize large quantities of cortisone from the diosgenin in yams resulted in a rapid drop in price to US $6 per gram, falling to $ per gram by 1980. Percy Julian's research also aided progress in the field. [46] The exact nature of cortisone's anti-inflammatory action remained a mystery for years after, however, until the leukocyte adhesion cascade and the role of phospholipase A2 in the production of prostaglandins and leukotrienes was fully understood in the early 1980s.

Two isozymes of 11beta-hydroxysteroid dehydrogenase (11beta-HSD1 and 11beta-HSD2) catalyse the interconversion of hormonally active cortisol and inactive cortisone. The enzyme evolved from a metabolic pathway to a novel mechanism underpinning human disease with the elucidation of the role of the type 2 or 'kidney' isozyme and an inherited form of hypertension, 'apparent mineralocorticoid excess'. 'Cushing's disease of the kidney' arises because of a failure of 11beta-HSD2 to inactivate cortisol to cortisone resulting in cortisol-induced mineralocorticoid , 11beta-HSD1 has been linked to human obesity and insulin resistance, but also to other diseases in which glucocorticoids have historically been implicated (osteoporosis, glaucoma). Here, the activation of cortisol from cortisone facilitates glucocorticoid hormone action at an autocrine level. The molecular basis for the putative human 11beta-HSD1 'knockout'--'cortisone reductase deficiency'--has recently been described, an observation that also answers a long standing conundrum relating to the set-point of 11beta-HSD1 activity. In each case, these clinical studies have been underpinned by studies in vitro and the manipulation of enzyme expression in vivo using recombinant mouse models.

The full data set consisted of > 60,000 entries, including binding, agonist, and antagonist information for ~ 15,000 unique chemical structures. For the purpose of this project, this data set was cleaned and made more consistent by removing  in vivo  data, cytotoxicity information, and all ambiguous entries (missing values, undefined/nonstandard end points, and unclear units). Only 7,547 chemical structures from the experimental evaluation set that overlapped with the CERAPP prediction set, for a total of 44,641 entries, were kept and made available for download on the . EPA ToxCast™ Data web site ( https:///research/COMPTOX/CERAPP_ , ) ( . EPA 2016 ). The non-CERAPP chemicals were excluded from the evaluation set (see “Chemical Structure Curation” section). Then, all data entries were categorized into three assay classes: ( a ) binding, ( b ) reporter gene/transactivation, or ( c ) cell proliferation. The training set end point to model is the ER model AUC that parallels the corresponding individual assay AC 50  values, and therefore all units for activities in the experimental data set were converted to μM to have approximately equivalent concentration–response values for the evaluation set. Chemicals with cell proliferation assays were considered as actives if they exceeded an arbitrary threshold of 125% proliferation. For entries where testing concentrations were reported in the assay name field, those values were converted to μM and considered as the AC 50  value if the compound was reported as active. All inactive compounds were arbitrarily assigned an AC 50  value of 1 M.

An example of an acute hepatitis-like syndrome arising after pulse methylprednisolone therapy.  These episodes arise typically 2 to 4 weeks after a third or fourth cycle of pulse therapy, and range in severity from an asymptomatic and transient rise in serum aminotransferase levels to an acute hepatitis and even fulminant hepatic failure.  In this instance, the marked and persistent rise in serum enzymes coupled with liver histology suggesting chronic hepatitis led to a diagnosis of new-onset autoimmune hepatitis, despite the absence of serum autoantibodies or hypergammaglobulinemia.  Autoimmune hepatitis may initially present in this fashion, without the typical pattern of serum autoantibodies during the early, anicteric phase.  The diagnosis was further supported by the prompt improvements in serum enzymes with prednisone therapy.  The acute hepatitis-like syndrome that can occur after pulses of methylprednisolone is best explained as a triggering of an underlying chronic autoimmune hepatitis caused by the sudden and profound immunosuppression followed by rapid withdrawal.  This syndrome can be severe, and fatal instances have been reported.  Whether reinitiation of corticosteroid therapy with gradual tapering and withdrawal is effective in ameliorating the course of illness is unclear, but anecdotal reports such as this one suggest that they are beneficial and should be initiated promptly on appearance of this syndrome.  Long term follow up of such cases is also necessary to document that the autoimmune hepatitis does not relapse once corticosteroids are withdrawn again.

Mild nasopharyngeal irritation following the use of beclomethasone aqueous nasal spray has been reported in up to 24% of patients treated, including occasional sneezing attacks (about 4%) occurring immediately following use of the spray. In patients experiencing these symptoms, none had to discontinue treatment. The incidence of transient irritation and sneezing was approximately the same in the group of patients who received placebo in these studies, implying that these complaints may be related to vehicle components of the formulation.

Corticosteroid receptor hypothesis

corticosteroid receptor hypothesis

An example of an acute hepatitis-like syndrome arising after pulse methylprednisolone therapy.  These episodes arise typically 2 to 4 weeks after a third or fourth cycle of pulse therapy, and range in severity from an asymptomatic and transient rise in serum aminotransferase levels to an acute hepatitis and even fulminant hepatic failure.  In this instance, the marked and persistent rise in serum enzymes coupled with liver histology suggesting chronic hepatitis led to a diagnosis of new-onset autoimmune hepatitis, despite the absence of serum autoantibodies or hypergammaglobulinemia.  Autoimmune hepatitis may initially present in this fashion, without the typical pattern of serum autoantibodies during the early, anicteric phase.  The diagnosis was further supported by the prompt improvements in serum enzymes with prednisone therapy.  The acute hepatitis-like syndrome that can occur after pulses of methylprednisolone is best explained as a triggering of an underlying chronic autoimmune hepatitis caused by the sudden and profound immunosuppression followed by rapid withdrawal.  This syndrome can be severe, and fatal instances have been reported.  Whether reinitiation of corticosteroid therapy with gradual tapering and withdrawal is effective in ameliorating the course of illness is unclear, but anecdotal reports such as this one suggest that they are beneficial and should be initiated promptly on appearance of this syndrome.  Long term follow up of such cases is also necessary to document that the autoimmune hepatitis does not relapse once corticosteroids are withdrawn again.

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