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PubMed2000

Simultaneous determination of endogenous and 13C-labelled cortisols and cortisones in human plasma by stable isotope dilution mass spectrometry.

This study describes a capillary GC-MS method for the simultaneous determination of endogenous cortisol and cortisone and their 13C-labelled analogues, [1,2,4,19-13C4]cortisol (cortisol-13C4) and [1,2,4,19-13C4]cortisone (cortisone-13C4), in human plasma. [1,2,4,19-13C4,1,1,19,19,19-2H5]Cortisol (cortisol-13C4,2H5) and [1,2,4,19-13C4,1,1,19,19,19-2H5]cortisone (cortisone-13C4,2H5) were used as analytical internal standards. A double derivatization (bismethylenedioxy-pentafluoropropionate, BMD-PFP) with good GC behavior was employed for the GC-MS analysis of cortisol and cortisone. Quantitation was carried out by selected-ion monitoring of the molecular ions ([M]+*) of the BMD-PFP derivatives of cortisol and cortisone. The sensitivity limit of the present GC-MS-SIM method was found to be 150 pg per injection for cortisol (s/n=5.0) and 50 pg for cortisone (s/n=8.1). The within-day reproducibility in which the amounts of unlabelled and labelled cortisols and cortisones determined were in good agreement with the actual amounts added, the relative errors being less than 3.07%. The inter-assay coefficients of variation (C.V.) were less than 1.80% for unlabelled and labelled cortisols and cortisones.

Carbon Isotopes↗

PubMed1972

Evaluation of the rate-limiting steps in the pathway of glucose metabolism in kidney cortex of normal, diabetic, cortisone-treated and growth hormone-treated rats.

1. The activities of gluconeogenic and glycolytic enzymes and the concentrations of citrate, ammonia, amino acids, glycogen, glucose 6-phosphate, acetyl-CoA, lactate and pyruvate were measured in kidney cortex of normal, diabetic, cortisone-treated and growth hormone-treated rats. 2. In kidney cortex of diabetic, cortisone-treated and growth hormone-treated rats the activities of glucose 6-phosphatase (EC 3.1.3.9), fructose 1,6-diphosphatase (EC 3.1.3.11) and phosphopyruvate carboxylase (EC 4.1.1.32) were increased. 3. The activities of glutamate dehydrogenase (EC 1.4.1.3), alanine aminotransferase (EC 2.6.1.2), aspartate aminotransferase (EC 2.6.1.10) and pyruvate carboxylase (EC 6.4.1.1) were increased in diabetic and cortisone-treated rats. In growth hormone-treated rats the activity of aspartate aminotransferase was depressed but those of the other three enzymes were unchanged. 4. The activity of hexokinase (EC 2.7.1.1) was not altered in any of these conditions. Phosphofructokinase (EC 2.7.1.11) activity was depressed only in growth hormone-treated rats. Pyruvate kinase (EC 2.7.1.40) activity was depressed in cortisone-treated and growth hormone-treated rats but unchanged in diabetic rats. 5. Amino acids, acetyl-CoA and glucose 6-phosphate contents were increased in rat kidneys in all these three conditions. Ammonia content was increased in diabetic and cortisone-treated rats but was markedly diminished in growth hormone-treated rats. 6. The [lactate]/[pyruvate] ratio was elevated in diabetic and cortisone-treated rats but unchanged in growth hormone-treated rats. Citrate content was increased in the kidney cortex of diabetic and growth hormone-treated rats but was unchanged in cortisone-treated rats. The activity of ATP citrate lyase (EC 4.1.3.8) was depressed in diabetic and growth hormone-treated rats but was increased in cortisone-treated rats. 7. Glycogen content was moderately elevated in growth hormone-treated rats and markedly elevated in diabetic rats, whereas no change in glycogen content was observed in cortisone-treated rats. Glycogen synthetase (EC 2.4.1.11) activity was unchanged in all these three conditions. Phosphorylase (EC 2.4.1.1) activity was not affected in cortisone-treated rats but was depressed in diabetic and growth hormone-treated rats.

Alanine Transaminase↗

PubMed1991

Thyroxine and cortisone cooperate to modulate postnatal intestinal enzyme differentiation in the rat.

Interactions of cortisone and thyroxine (T4) in modulating jejunal sucrase and lactase expression were studied in rats during early postnatal life. Cortisone (50 micrograms/g body wt) precociously induced sucrase activity in days 5-16 rats and enhanced activity thereafter until day 22. T4 (1 microgram/g) plus cortisone evoked greater sucrase expression in day 9 or younger rats. T4 did not induce sucrase expression until day 13. Lactase activity was enhanced in rats younger than day 9 by cortisone, and this effect was abolished when T4 was added. In days 19 and 22 rats, cortisone depressed lactase; with T4, lactase activity was further decreased. T4 alone did not suppress lactase activity until day 19. Quantitation of jejunal enzyme content showed that sucrase catalytic activity was higher in day 22 than 19 or younger rats and lower in rats given T4 than cortisone. In contrast, lactase activity remained constant in all animal groups. In vivo [35S]methionine-labeling studies using day 9 rats showed that cortisone induced de novo synthesis of sucrase and increased 35S incorporation into lactase. Cortisone plus T4 increased 35S incorporation into sucrase further and significantly increased 35S incorporation into lactase. We conclude that 1) cortisone and T4 cooperatively stimulate sucrase expression and reduce lactase activity during early postnatal life and 2) reduction in lactase activity accompanied by increase in lactase synthesis suggests that cortisone and T4 regulate lactase activity at posttranslational level.

Aging↗

PubMed1999

Assessment of the follicular cortisol:cortisone ratio.

Cortisol and cortisone concentrations in serum and follicular fluid (FF) from women undergoing in-vitro fertilization (IVF) treatment were monitored. Four groups were included: group 1, women in their natural menstrual cycle having an endogenous mid-cycle surge of gonadotrophins; group 2, women in their natural menstrual cycle receiving human chorionic gonadotrophin (HCG) for ovulation induction; group 3, women receiving exogenous gonadotrophins for ovarian stimulation and HCG for ovulation induction; and group 4, women receiving exogenous gonadotrophins for ovarian stimulation, follicles being aspirated immediately before administration of HCG. In this study, 12 follicles contained oocytes which resulted in clinical pregnancy after IVF. Cortisone concentrations were significantly higher in FF compared with that of matched serum samples, while the opposite was observed for cortisol, resulting in cortisol:cortisone ratios being significantly lower in FF compared with serum. FF from group 4 showed significantly higher cortisone concentrations than FF from each of the other three groups. FF from group 1 showed significantly higher cortisone concentrations and significantly lower cortisol:cortisone ratios in comparison with groups 2 and 3. None of the observed parameters pinpointed any of the follicles containing oocytes which resulted in a clinical pregnancy. The intrafollicular concentrations of cortisol and cortisone suggest that pre-ovulatory follicles actively convert cortisol to cortisone. Neither FF concentrations of cortisol and cortisone nor the cortisol:cortisone ratio seem to reflect implantation potential of the derived pre-embryos.

Adult↗

PubMed2006

The effect of insulin-like growth factor I on healing of colonic anastomoses in cortisone-treated rats.

PURPOSE: This study was designed to investigate whether intraperitoneally injected insulin-like growth factor I is able to protect colonic healing from the adverse effects of hydrocortisone therapy. METHODS: Eighty female Wistar rats were randomized into four groups (20 rats each). After resection of a segment of transverse colon, an end-to-end anastomosis was performed. Hydrocortisone (5 mg/kg body weight) was injected intramuscularly in rats of cortisone (Group B) and insulin-like growth factor I + cortisone (Group D) groups once daily for seven days before and after the operation. Insulin-like growth factor I (2 mg/kg body weight) was intraperitoneally injected in rats of the insulin-like growth factor I (Group C) and the insulin-like growth factor I + Cortisone (Group D) groups immediately after operation and on the second, fourth, and sixth postoperative days. Rats were killed on the seventh postoperative day. Anastomoses were graded macroscopically and histologically, and bursting pressures and anastomotic hydroxyproline levels were recorded. Statistical analyses were performed by using Fisher's exact test for the comparison of proportions and ANOVA for the comparison of means among groups with subsequent post-hoc analysis using Bonferroni correction. RESULTS: Leakage rate was significantly higher in the cortisone (Group B) group. Bursting pressures were significantly lower in the cortisone group, whereas they were significantly higher in the insulin-like growth factor I and insulin-like growth factor I + cortisone groups (Group C and D). Histology revealed a significant decrease of inflammatory cell infiltration, neoangiogenesis, and fibroblast activity in the cortisone group compared with the control group, whereas these parameters were significantly higher in the insulin-like growth factor I and insulin-like growth factor I + cortisone groups. Hydroxyproline levels were significantly higher in the insulin-like growth factor I and insulin-like growth factor I + cortisone groups. CONCLUSIONS: Hydrocortisone inhibits the healing of colonic anastomoses. However, insulin-like growth factor I given intraperitoneally mediates the deleterious effects of cortisone and protects colonic healing in rats.

Anastomosis, Surgical↗

PubMed1999

Assessment of the follicular cortisol:cortisone ratio

Journal Article↗

PubMed1981

Cortisone-induced cleft palate in A/J mice: failure of palatal shelf contact.

Although cortisone treatment for induction of cleft palate in mice has been shown to delay the time of palatal shelf elevation, the effects of delayed elevation of shelf contact have not been critically evaluated in a cortisone-sensitive mouse strain. The objective of this study was to evaluated palatal development in cortisone-treated A/J mice in order to determine whether the shelves make contact upon elevation. Morphometric analysis of frozen sections revealed that cortisone-treated shelves were smaller than control shelves with apparent reductions in both the content of extracellular matrix and the number of cells. At a light microscopic level, thinning of medial epithelium in cortisone-treated palates appeared similar to that in untreated palates with spontaneous cleft lip and palate. Shelf elevation was delayed by approximately 12 hours and only half of the cortisone-treated palates achieved complete horizontal positioning of the shelves in all regions of the palate. Immediately after elevation, all control palates had extensive vertical contact along the complete length of the palate. In contrast, approximately 20% of the cortisone-treated fetuses had contact between the shelves in the middle palate region only, with the mean area of contact only 20% as large as in control fetuses. As result, the net shelf contact in all the cortisone-treated fetuses was only 4% of the potential contact shown in control fetuses. Therefore, failure of the palatal shelves to elevate and make extensive contact appeared to be the major factor contributing to cortisone-induced cleft palate in A/J mice.

Animals↗

PubMed2004

Cortisol and cortisone analysis in serum and plasma by atmospheric pressure photoionization tandem mass spectrometry.

OBJECTIVES: Cortisol metabolism is controlled by 11beta-hydroxysteroid dehydrogenase (11beta-HSD) isoenzymes, which interconvert cortisol and cortisone. Accurate measurement of the cortisol and cortisone concentrations and their ratio provide useful information about 11beta-HSD activity. METHODS: Cortisol and cortisone were extracted with methyl-tert-butyl ether from 100 microl of serum or plasma. The extract was evaporated, reconstituted with mobile phase, and analyzed by tandem mass spectrometry using a photoionization interface. The transitions monitored were: m/z 363 to 121 and 363 to 97 for cortisol, 361 to 163 and 361 to 105 for cortisone. RESULTS: Within-run and between-run coefficients of variation were less than 6% and 12%; 14% and 22%; 11% and 21% for cortisol, cortisone, and their ratio, respectively. The limit of detection was 1 microg/l for cortisol and 5 microg/l for cortisone. Normal ranges for cortisol and cortisone concentration and for their ratio in plasma (n = 120) determined as the central 95% were 33-246 microg/l for cortisol, 8-27 microg/l for cortisone, and 0.081-0.301 for the cortisone/cortisol ratio. CONCLUSIONS: We developed a simple sensitive method for cortisol and cortisone analysis in plasma and serum that uses a small sample volume. The method is very specific, fast, does not have any known interference, and is useful for diagnosis of variety of disease and pathologic conditions.

11-beta-Hydroxysteroid Dehydrogenases↗

PubMed2004

Detection of physiological concentrations of cortisol and cortisone in human hair.

OBJECTIVE: Since the 1960s, glucocorticoids are used by athletes to improve their performances. Their use is restricted in sports. Hair can document chronic abuse and can be therefore a complementary matrix for doping control. We have developed a new extraction, purification, and separation technique using liquid chromatography and mass spectrometry for the identification and quantification of two endogenous glucocorticoids: cortisol and cortisone. METHODS: Qualitative and quantitative investigations were achieved with 44 hair samples (17 males, 27 females; age ranging from 2 to 90 years). Hair strands were washed in methylene chloride, the first two centimeters of the strand were cut and pulverized in a ball mill. The powdered hair was incubated in 2 mL Soerensen buffer, pH 7.6, for 16 h at 40 degrees C, in the presence of cortisol-d3 as an internal standard. Purification of the incubation medium was achieved on SPE C18 Isolute extraction columns followed by an alkaline liquid-liquid extraction with diethylether. The eluate was evaporated to dryness and resuspended in 25 microL of acetonitrile/ammonium formiate (1:1,v/v). The chromatography was operated on a LC Packings Superba Nucleosil C18 column using a linear gradient of acetonitrile from 30% to 70% in 10 min. The detector was a Perkin Elmer Sciex API 100 mass spectrometer. The detector's response was linear for cortisol and cortisone concentrations ranging from 1 to 500 pg/mg. Extraction recovery at 50 pg/mg was 74% for cortisol and 32% for cortisone. Repeatability (CV values n = 8) at 7 pg/mg cortisol and at 50 pg/mg cortisone were 11% in both cases. Limit of detection and limit of quantification were 1 and 5 pg/mg, for both compounds, respectively. RESULTS: Cortisol concentrations in hair ranged from 5 to 91 pg/mg (mean 18 pg/mg). Cortisone concentrations in hair ranged from 12 to 163 pg/mg (mean 70 pg/mg). No influence of hair colour could be found. Influence of sex on cortisone concentrations seems possible but could not be statistically demonstrated. Finally, cortisone concentrations in hair are significantly higher before the age of 20. Incorporation of cortisol and cortisone in hair could follow a passive diffusion through sweat after conversion of part of cortisol to cortisone by Type 2 11-beta-Hydroxysteroid-dehydrogenase in sweat glands. This issue was documented by these analyses.

Acetonitriles↗

PubMed1999

Relationship between ovarian cortisol:cortisone ratios and the clinical outcome of in vitro fertilization and embryo transfer (IVF-ET).

OBJECTIVE: Previously, we have reported an association between low levels of intraovarian cortisol metabolism, mediated by 11beta-hydroxysteroid dehydrogenase (11betaHSD), and the establishment of pregnancies by in vitro fertilization and embryo transfer (IVF-ET). The objective of the present study was to investigate the relationship between the clinical outcome of IVF-ET and the intraovarian concentrations of cortisol and cortisone and the cortisol:cortisone ratios in random samples of ovarian follicular fluid (FF). DESIGN: Retrospective, double-blind correlation analyses. PATIENTS: FF samples (n = 41) were obtained from 23 women undergoing gonadotrophin-stimulated IVF-ET cycles at the Cardiff Assisted Reproduction Unit. MEASUREMENTS: Clinical pregnancy was confirmed by ultrasonography. Intrafollicular steroid concentrations were measured by radioimmunoassays. RESULTS: Concentrations of both cortisol and cortisone were significantly lower in FF samples obtained from 6 patients that conceived than in samples obtained from 17 patients that did not achieve pregnancy (cortisol (mean +/- SEM) = 304 +/- 29 vs. 407 +/- 26 nmol/l, P = 0. 0411; cortisone = 32 +/- 3 vs. 65 +/- 7 nmol/l, P = 0.0002). Intrafollicular cortisol:cortisone ratios were significantly higher in samples from conception cycles than in those samples obtained from nonconception cycles (9.7 +/- 0.7 vs. 6.9 +/- 0.5, respectively, P = 0.0060). Whereas 5 of 10 women with intrafollicular cortisol:cortisone ratios greater than the outcome-independent mean of 7.7 became pregnant, only 1 of the 13 patients with intrafollicular cortisol:cortisone ratios < 7.7 conceived (chi2 = 5. 247, P = 0.0220). CONCLUSIONS: Concentrations of both cortisol and cortisone were significantly lower in FF samples obtained from patients that conceived by IVF-ET than in those obtained from nonconception cycles. Conception by gonadotrophin-stimulated IVF-ET was associated with an elevated intrafollicular ratio of cortisol:cortisone, consistent with a low level of intraovarian cortisol oxidation by 11betaHSD.

Buserelin↗

PubMed2003

The effects of growth hormone deficiency and replacement on glucocorticoid exposure in hypopituitary patients on cortisone acetate and hydrocortisone replacement.

OBJECTIVE: 11 beta-hydroxysteroid dehydrogenase type 1 (11 beta HSD1) converts inactive cortisone to active cortisol. 11 beta HSD1 activity is increased in GH deficiency and inhibited by GH and IGF-I in acromegaly. However it is not known whether these changes in cortisol metabolism exert significant effects during hydrocortisone therapy, and the effect has not been studied in patients taking cortisone acetate. We have studied the effect of GH induced 11 beta HSD1 inhibition in hypopituitary adults with severe GH deficiency to determine whether this inhibition has a different magnitude of effect when patients are taking different forms of glucocorticoid replacement therapy. DESIGN, PATIENTS AND MEASUREMENTS: We have taken the ratio of 11-hydroxy/11-oxo cortisol metabolites (Fm/Em), an established measure of net 11 beta HSD activity to reflect the likely balance of cortisol to cortisone exposure in tissues expressing 11 beta HSD1, principally the liver and adipose tissue. We recruited 10 hypopituitary adults all on established glucocorticoid replacement therapy, but who were not receiving GH. Patients were treated with their standard hydrocortisone therapy for one week and an equivalent dose of cortisone acetate in its place for one week in random order. Serial serum cortisol assessments and urine steroid profiles were performed on each treatment. All patients were then established on GH therapy for at least three months before the two-week cycle was repeated. Fm/Em was also measured in a control population (20F, 20M). RESULTS: Prior to GH, the ratio Fm/Em was greater with hydrocortisone compared with cortisone acetate replacement (1.17 +/- 0.28 and 0.52 +/- 0.09 respectively, P < 0.001) or with normal subjects (normal males: 0.81 +/- 0.24, females 0.66 +/- 0.14). Following GH replacement Fm/Em fell in patients on hydrocortisone and cortisone acetate (Pre-GH: 0.84 +/- 0.40, Post-GH: 0.70 +/- 0.34, P < 0.05) confirming the inhibition of 11 beta HSD1 by GH/IGF-I. Conversely, the ratio of urinary free cortisol/cortisone did not change indicating unchanged 11 beta HSD2 activity. Mean circulating cortisol also fell in all subjects after GH. This effect was greater during cortisone acetate treatment (-18.7%, P < 0.0001), than during hydrocortisone replacement (-10.9%, P < 0.05). CONCLUSIONS: Our data suggest that tissue exposure to glucocorticoid is supra-physiological in hypopituitary patients with untreated GH deficiency taking hydrocortisone replacement therapy. This situation is ameliorated by GH replacement therapy. However, local and circulating cortisol concentrations are more vulnerable to the inhibitory effect of GH on 11 beta HSD1 in patients taking cortisone acetate, such that serum cortisol assessments should be made in patients taking cortisone acetate after GH therapy to ensure that glucocorticoid replacement remains adequate.

11-beta-Hydroxysteroid Dehydrogenase Type 1↗

PubMed2005

Circulating cortisone levels are associated with biochemical markers of bone formation and lumbar spine BMD: the Hertfordshire Cohort Study.

OBJECTIVE: Cortisone is an endogenous corticosteroid that has negligible intrinsic glucocorticoid activity but can be converted to the active corticosteroid cortisol by the enzyme 11beta-hydroxysteroid dehydrogenase type 1 (11beta-HSD1). 11beta-HSD1 is expressed in osteoblasts and may play a role in determining susceptibility to glucocorticoid-induced osteoporosis. In intact osteoblasts enzyme activity, and thus cortisol generation, is dependent on substrate concentration with an almost linear increase in activity across the physiological range. We have therefore attempted to measure the impact of 11beta-HSD1 activity on bone in vivo by examining the association of circulating cortisone with bone markers, bone mineral density (BMD) and bone loss in a cohort of women and men. DESIGN AND SUBJECTS: Baseline cross-sectional association study involving 135 women and 171 men aged 61-73 years from the Hertfordshire Cohort Study and a 4 year follow-up study examining changes in BMD. MEASUREMENTS: Serum cortisone, cortisol and osteocalcin, and urinary type I collagen cross-linked N-telopeptide (NTX) were measured at baseline. BMD at spine and hip was measured at baseline and 4 years later. RESULTS: In men serum cortisone levels were negatively correlated with serum osteocalcin (r = -0.20, P = 0.01); a similar relationship was seen in women (r = -0.16, P = 0.06). No correlation was seen between serum cortisone and urinary NTX (r = 0.03, P = 0.74 for women; r = -0.03, P = 0.72 for men). A negative correlation was observed between serum cortisone and spine BMD in women (r = -0.18, P = 0.04); a similar relationship was also seen in men (r =-0.14, P = 0.07). However, cortisone did not correlate with BMD at the femoral neck or total hip or changes in BMD at any site over time. In analyses adjusted for adiposity, osteoarthritis grade and a range of life-style variables, these relationships did not change substantially. All these relationships were independent of cortisol concentrations. CONCLUSIONS: The most plausible explanation for the association of circulating cortisone levels with osteocalcin is the presence of 11beta-HSD1 activity within osteoblasts. The measurement of serum cortisone may independently give insights into the action of glucocorticoids on bone.

Aged↗

PubMed1986

Inhibition of vascularization in rabbit corneas by heparin: cortisone pellets.

The purpose of this work was to study the effectiveness of heparin plus cortisone, and of cortisone alone in control of corneal vascularization in rabbit eyes. Corneal vascularization was induced by de-epithelialization of the cornea and limbus and part of the bulbar conjunctiva with concurrent trephination and excision of a central 2-mm diameter corneal button. Inhibition of vascularization by polymer pellets impregnated with heparin (Panheprin, Abbott Laboratories; Chicago, IL) and cortisone, or neither drug was studied by implanting the pellets into the eyes at the time of injury and following the eye clinically and histologically. Wounded corneas with empty pellets developed vascularization extending from the limbus to the central cornea within 3 wk (n = 10). In other wounded eyes, heparin:cortisone pellets prevented vascularization (n = 10) while cortisone pellets slowed, but did not totally inhibit vascularization (n = 6). In other eyes, clear autografts were transplanted into vascularized eyes; and the ability of the drug-impregnated pellets to inhibit grafts vascularization was evaluated. In eyes with heparin:cortisone pellets inserted into the donor button at the time of keratoplasty, the autografts remained clear for at least 6 wk (n = 10) but subsequently vascularized if the sutures were not removed, while cortisone pellets slowed but did not block vascularization (n = 6). If heparin:cortisone pellets were inserted into the vascularized host tissue, rather than into the donor button, vascularization of the graft occurred (n = 6). Thus, heparin (Panheprin, Abbott Laboratories; Chicago IL) plus cortisone inhibited vascularization in rabbit cornea in the models studied: The effect of other commercially available heparins remains to be studied.

Animals↗

PubMed2003

Effect of prenatal cortisone on spontaneous bacterial translocation from gastrointestinal tract in neonatal rat.

The immature host is prone to the passage of bacteria across the gut mucosal barrier. Corticosteroids accelerate the maturation of the intestinal mucosa and alter the composition of the gut bacterial flora. The present study was performed to assess the effect of prenatal cortisone on bacterial translocation in the neonatal rat. Time-pregnant Sprague Dawley rats were randomized on the 19th day of gestation for intraperitoneal injection of either 20 mg/100 g body weight of hydrocortisone or saline. Rats delivered spontaneously and the offspring were suckled ad libitum by the dam. Rat pups (N = 82) were killed 1 or 9 days after delivery. Mesenteric lymph nodes, liver, heart blood, and the terminal ileal loop were excised and quantitatively analyzed for bacteria. After one day, the proportion of rats with positive translocation was not significantly different between the two treatment groups (saline 62%, cortisone 80%, P = NS). By day 9, translocation had increased in the saline group (P = 0.03 vs day 1), did not significantly change in the cortisone group, and was significantly lower in rats treated with cortisone compared with the saline control (saline 90%, cortisone 60%, P = 0.02). The decrease in bacterial translocation after treatment with cortisone was associated with significantly lower total bacterial counts in the ileum (P < 0.05). Cortisone did not reduce bacterial counts in extraintestinal organs with positive translocation. In conclusion, prenatal treatment with cortisone reduces the incidence of spontaneous bacterial translocation from the intestine but not the concentration of translocated bacteria in extraintestinal organs of 9-day-old rats. Cortisone-induced changes of the intestinal microflora may have contributed to the reduction in translocation frequency.

Animals↗

PubMed1964

EFFECTS OF BACTERIAL ENDOTOXINS ON METABOLISM. VII. ENZYME INDUCTION AND CORTISONE PROTECTION.

Cortisone acetate administered to mice at the same time as either the LD(50) or 2 x LD(50) of endotoxin significantly protected against lethality. Delaying the injection of cortisone to 1, 2, or 4 hours after that of endotoxin resulted in loss of protection with the possible exception of a 1 hour delay with the LD(50) of endotoxin. Associated with this loss of protection was the failure of the hormone to induce liver tryptophan pyrrolase. Normal mice given only cortisone showed an increase in enzyme activity nearly three times that of control values when assays were carried out either 4 or 17 hours after the hormone was given. Endotoxin-poisoned mice showed normal levels of enzyme activity with concurrent injection of cortisone but depressed levels of enzyme when the cortisone injection was delayed for only 1 hour or more. Apparently, therefore, enzyme induction (or maintenance) is related to survival in endotoxin poisoning. In line with this hypothesis was the observation that inhibitors of enzyme (protein) synthesis were found to potentiate the lethal action of endotoxin and to prevent the protective effect of cortisone. The inhibitors employed were actinomycin D, ethionine, 2-thiouracil, and 8-azaguanine. Activity of liver tryptophan pyrrolase was lowered by endotoxin and elevated by cortisone. When the two were given concurrently, normal enzyme activity was maintained. Chloramphenicol, an active inhibitor of protein synthesis in microorganisms but with limited effect in mammals, was without observable influence in these respects. Mice 18 hours postinfection with Salmonella typhimurium, strain SR-11, given at a level that caused first deaths on the 3rd day, had a lower than normal activity of liver tryptophan pyrrolase and responded to cortisone induction with a smaller increase in enzyme level than that found in control mice. Each is characteristic of endotoxin poisoning. Animals 42 hours postinfection were free of these signs of endointoxication, an observation in agreement with earlier experiments where other measures of endotoxin were employed.

Animals↗

PubMed1979

Biphasic rate of synthesis of glycoconjugates, phospholipids and DNA in concanavalin A-stimulated mouse thymocytes. Involvement of cortisone-sensitive and -resistant subpopulations.

The time course of the rate of labeling of membrane components (phospholipids, glycolipids and glycoproteins) and DNA was followed in concanavalin A-stimulated CBA/J mouse thymocyte cultures. Two peaks of stimulated biosynthetic activity were noted, the first at the beginning of the cultivation and the second about 25 h later. Both early and late peaks of biosynthesis of membrane components were accompanied by blast transformation and were unimpeded by suppression of DNA synthesis by hydroxyurea. Cortisone-sensitive and cortisone-resistant thymocytes were prepared by selective agglutination of the cortisone-sensitive cells with peanut agglutinin (Reisner et al. Cell. Immunol. 1976. 25: 129) or cortisone treatment of the animals. Cortisone-sensitive cells responded early, while the cortisone-resistant population gave only the late response. The autoradiographic patterns from sodium dodecyl sulfate polyacrylamide gels of [3H]fucose or [3H]galactose-labeled glycoproteins from early and late labeling cells, and cortisone-resistant cells, were compared. Late-labeling and cortisone-resistant cells gave indistinguishable patterns, but differed significantly in their patterns from early-labeling cells. It is concluded that the two peaks of biosynthetic activity during the course of concanavalin A stimulation of thymocytes are caused by two different cell populations which require different times for maximal response and react independently of one another.

Animals↗

PubMed1989

A scanning electron microscope study of fetal eyelid closure accelerated by cortisone in SWV/Bc mice.

Eyelid closure occurs earlier in SWV/Bc and CBA/J mouse fetuses whose mothers were treated with cortisone on day 14 of gestation than it does in fetuses from untreated mothers. Similar treatment prevents the open-eyes defect of lidgap-Miller mutant mice, but examination by scanning electron microscope (SEM) has shown differences in the periderm of the closing eyelids of the cortisone-treated mutant compared with those of untreated genetically normal fetuses. (Untreated mutant eyelids remain wide open and very abnormal). The present study has examined at the SEM level the accelerated eyelid closure of cortisone-treated normal strain, SWV/Bc, fetuses to investigate whether the differences from normal in the eyelids of treated lidgap-Miller fetuses are part of the mechanism of the cortisone "cure." At the SEM level, cortisone-accelerated eyelid closure of SWV/Bc fetuses is indistinguishable from that in untreated fetuses. This suggests that the early eyelid closure induced by cortisone in normal strain fetuses represents acceleration of the normal coordinated sequence of events that leads to closure, rather than an abnormality that fortuitously leads to closure. The data also indicate that the cellular abnormalities seen previously in treated lidgap-Miller mutant fetuses are a combination of 1) abnormalities due to the mutation that are not completely reversed by cortisone and 2) normal developmental stages that have become concurrent with the cortisone-induced late closure in lidgap-Miller mutant fetuses.

Animals↗

PubMed1992

The cortisone era: aspects of its impact. Some contributions of the Merck Laboratories.

The announcement in 1949, by Hench at the Mayo Clinic, that cortisone had a dramatic beneficial effect on bed-ridden patients suffering from rheumatoid arthritis ushered in the cortisone era. This medical landmark was made possible by the prior steroid research of distinguished chemists and biologists in several countries. The first partial synthesis of cortisone by Sarett was the culmination of a worldwide chemical effort. This work ultimately enabled the process research department at Merck, under the direction of Max Tishler, to perform the 37-step conversion of deoxycholic acid to cortisone on a scale that made the initial clinical trials possible. In spite of the enormity of the project, and the fact that neither of two closely related analogs of cortisone had shown any interesting biological activity. Merck elected to embark on this synthetically challenging project. The clinical results reported in 1949, combined with the complexity of the partial synthesis, stimulated highly innovative research to discover new routes to cortisone and to cortisol, the active hormone. This research, particularly in the pharmaceutical industry in the United States, Mexico, and Europe, demonstrated, among other things, the value of microbial transformations in synthetic sequences. The recognition that the chronic administration of cortisol produces several unexpected side effects stimulated an intensive effort in many countries to discover an analog with an improved therapeutic index. This led to more novel chemistry and many analogs were discovered that proved to be more potent than cortisol. Prednisolone, discovered at the Schering Corporation, was the first compound that combined a high level of anti-inflammatory activity with reduced salt retention. Derek Barton contributed greatly to steroid research during the 1950s by applying creative structural thinking to systematize a host of seemingly unrelated chemical and biological observations. The cortisone era had a profound impact on drug discovery also, since it led to the logical application of steric and electronic concepts to medicinal chemistry. Last, but not least, the cortisone era taught medicinal chemists many important lessons about drug-receptor interactions.

Anti-Inflammatory Agents↗