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PubMed2006

[Effects of blockage of hypothalamic-pituitary-adrenal cortex axis by metyrapone and Jiawei Xiaoyao Pills on immune system in mice exposed to chronic emotional stress].

OBJECTIVE: To explore the effects of Jiawei Xiaoyao Pills (JWXYP) on immune system of mice exposed to chronic emotional stress, and to compare its effects with blockage of hypothalamic-pituitary-adrenal cortex axis (HPAA) by metyrapone. METHODS: Eighty male mice were randomly divided into eight groups: normal saline-treated group, normal saline-treated stress group, JWXYP-treated group, JWXYP-treated stress group, metyrapone-treated group, metyrapone-treated stress group, metyrapone and JWXYP-treated group and metyrapone and JWXYP-treated stress group. A box of electrical shock was used to induce chronic emotional stress in mice. The metyrapone was applied to blocking the HPAA. The JWXYP, a classical formula of traditional Chinese medicine, which can alleviate the damages caused by chronic emotional stress, was also used to compare its effects with that of metyrapone. The body weight, thymus index, rate of apoptosis in thymus, serum concentration of glucocorticoid, activity of natural killer cells, lymphocyte transmission rate of mice were all measured and examined after interventions. The pathological changes of thymus tissue were observed. RESULTS: The thymus index, activity of natural killer cells and lymphocyte transmission rate were lower while the rate of apoptosis in thymus as well as the severity degree of pathological damages in thymus tissue were increased in the different drug-treated stress groups as compared with those in the corresponding drug-treated groups without stress. The activity of natural killer cells and the lymphocyte transmission rate induced by lipopolysaccharide were increased while the serum concentration of glucocorticoid and the severity degree of pathological damages in thymus tissue were decreased in both the metyrapone-treated stress group and JWXYP-treated stress group as compared with those in the normal saline-treated stress group. The combined intervention of metyrapone and JWXYP did not show better effects on immune system in mice exposed to chronic emotional stress than single metyrapone or JWXYP intervention. CONCLUSION: Blockage of HPAA by metyrapone intervention shows a significant protective effect on immune system in mice exposed to chronic emotional stress, and the JWXYP also exerts a similar protective effect against damages induced by chronic emotional stress. The HPAA may be one of the action targets of protective effects of JWXYP.

Animals↗
PubMed1996

Effects of metyrapone on expression of CYPs 2C11, 3A2, and other 3A genes in rat hepatocytes cultured on matrigel.

Hepatocytes cultured on matrigel express many liver-specific functions, but the levels and activities of the predominant male-specific rat hepatic CYPs, 3A2 and 2C11, decline rapidly in culture. Metyrapone maintains the level of total cytochrome P450 of rat hepatocytes in primary culture, but the mechanism underlying this effect has not been completely elucidated. The present study sought to determine whether metyrapone acts solely to stabilise CYP proteins in rat hepatocytes cultured on matrigel, or whether it also influences mRNA levels of the encoding genes. Metyrapone maintained the level of total cytochrome P450 in cultured hepatocytes so that values were > 200% of those found in untreated control cells 24 hr after isolation. At this time, CYP3A2-mediated testosterone 6 beta-hydroxylation was approximately 7-fold higher in hepatocytes cultured in the presence of metyrapone than in control cells, and CYP2C11-dependent testosterone 2 alpha- and 16 alpha-hydroxylation activities were between 2 and 3-fold greater. The results inferred from catalytic activities were supported by immunoquantitation of CYP3A and 2C11 proteins. The trend of increased CYP protein levels in metyrapone-treated cells continued throughout the 48-hr culture period. In control cells, CYP3A2 and 2C11 mRNA levels fell abruptly in culture to reach values at 24 hr that were < 30% of those in freshly isolated cells; addition of metyrapone failed to arrest this fall. However, treatment of cells with metyrapone considerably elevated levels of one or more CYP3A subfamily mRNA species, as detected by a riboprobe based on the cDNA for CYP3A1 ("CYP3A1-like mRNA') that were demonstrated, by another riboprobe, not to be CYP3A2 or RNCYP3AM. RT-PCR of mRNA prepared from cultured hepatocytes, followed by restriction mapping of the cloned cDNAs was used to characterise the CYP3A induced by metyrapone. This revealed that elevated levels of the CYP3A1-like mRNA were attributable to induction of RL33/cDEX mRNA; there were no CYP3A1 cDNAs isolated from these cells. These data are interpreted as indicating that metyrapone stabilises the expression of cytochrome P450 in culture by both pre- and posttranslational mechanisms. The particular mechanism employed is gene-specific, whereby even the highly homologous genes CYP3A2, RL33/cDEX and, possibly, RNCYP3AM are subject to different types of regulation in the presence of metyrapone.

Animals↗
PubMed1994

Induction of rat hepatic glucocorticoid-inducible cytochrome P450 3A by metyrapone.

The bipyridyl compound metyrapone is a potent inhibitor of cytochromes P450, a gene superfamily of haemoproteins involved in the metabolism of many xenobiotics as well as endogenous compounds such as steroid hormones. Administration of metyrapone to male rats induces the expression of the cytochrome P450 sub-family 3A (CYP3A). In order to determine whether metyrapone was causing the induction of CYP3A by blocking endogenous glucocorticoid metabolism, CYP3A levels were examined in rat hepatocytes cultured in serum-free medium supplemented with hydrocortisone 21-hemisuccinate plus or minus metyrapone. Western blotting indicated that metyrapone alone induces CYP3A and that hydrocortisone 21-hemisuccinate is ineffective. However, hydrocortisone 21-hemisuccinate enhanced the levels of CYP3A induced by metyrapone. In contrast, glucocorticoid-inducible tyrosine aminotransferase (TAT) activity was unaffected by metyrapone but metyrapone enhanced the levels induced by hydrocortisone 21-hemisuccinate. An examination of the metabolism of hydrocortisone by rat hepatocytes in vitro indicated that metyrapone perturbed the catabolism of hydrocortisone under conditions which give rise to an enhancement of hydrocortisone 21-hemisuccinate and hydrocortisone-dependent TAT induction. However, evidence is presented to suggest that such a perturbation of hydrocortisone metabolism could not account for the glucocorticoid potency amplifying property of metyrapone. Thus the induction of CYP3A and the enhancement of glucocorticoid-mediated TAT induction appears not to be associated with any perturbation in glucocorticoid metabolism but with some other as yet undefined mechanism(s).

Animals↗
PubMed1998

Partial reversal of stress-induced behavioral sensitization to amphetamine following metyrapone treatment.

Several studies indicate that blockade of stress-induced corticosterone secretion prevents the development of stress-induced sensitization to the behavioral effects of stimulants. The present study examined whether chronic blockade of corticosterone synthesis with metyrapone could reverse stress-induced amphetamine sensitization in rats. Restraint stress in cylindrical chambers, 2 times 30 min/day for 5 days over an 8-day schedule, was used as the stressor. Following completion of the stress protocol, animals were cannulated with microdialysis guide cannulae over the nucleus accumbens, and then treated with either metyrapone (50 mg/kg, i.p.) or vehicle (1 ml/kg) for 7 days. On the seventh day, animals were implanted with microdialysis probes in the nucleus accumbens, and on the following day, all animals were tested for their locomotor, stereotypy, and nucleus accumbens dopamine and DOPAC release responses to an injection of saline followed 60 min later by d-amphetamine (1.5 mg/kg, i.p.). Neither stress or metyrapone treatment had an effect on the behavioral or dopamine release response to saline. However, amphetamine-stimulated locomotion and stereotypy were strongly enhanced, while amphetamine-stimulated dopamine release response was slightly enhanced (significant only by drug x time interaction), in stressed animals. Metyrapone treatment reduced the stress-induced increase in the locomotor, but not stereotypy, response to amphetamine. In contrast, the dopamine release response to amphetamine was enhanced in metyrapone-treated animals, in both stressed and non-stressed groups, while DOPAC levels were unaffected by treatment group. This augmentation was particularly evident in the stressed-metyrapone-treated animals. Furthermore, non-stressed animals showed an increased locomotor and stereotypy response to amphetamine after treatment with metyrapone. These findings indicate that metyrapone treatment can reverse, or inhibit the expression of, stress-induced sensitization to the behavioral effects of amphetamine. However, the ability of metyrapone treatment to enhance the behavioral (in non-stressed animals) and dopamine release (in non-stressed and stressed animals) responses to amphetamine indicate that chronic metyrapone treatment will produce stimulant sensitization when given alone.

Amphetamine↗
PubMed1991

Short and long-term responses to metyrapone in the medical management of 91 patients with Cushing's syndrome.

OBJECTIVE: To analyse the clinical and biochemical effects of metyrapone in the treatment of Cushing's syndrome. DESIGN: An evaluation of the standard clinical practice at one institution. PATIENTS: Ninety-one patients with Cushing's syndrome: 57 pituitary-dependent Cushing's disease, 10 adrenocortical adenomas, six adrenocortical carcinomas and 18 ectopic ACTH syndrome. MEASUREMENTS: The acute response to metyrapone was assessed by measuring cortisol, 11-desoxycortisol and ACTH at 0, 1, 2, 3, 4 hours after a test dose of 750 mg of metyrapone. The longer-term effect of metyrapone was judged by measuring serum cortisol at 0900, 1200, 1500, 1800, 2100 and sometimes 2400 h and calculating a mean. RESULTS: A test dose of 750 mg of metyrapone decreased serum cortisol levels within 2 hours in all groups of patients and this effect was sustained at 4 hours. At the same time, serum 11-desoxycortisol levels increased in all patients, while plasma ACTH increased in patients with pituitary Cushing's disease and the ectopic ACTH-syndrome. Fifty-three patients with Cushing's disease were followed on short-term metyrapone therapy (1 to 16 weeks) before other more definitive therapy. Their mean cortisol levels (median 654 nmol/l, range 408-2240) dropped to the target range of less than 400 nmol/l in 40 patients (75%) on a median metyrapone dose of 2250 mg/day (range 750-6000). Metyrapone was given long term in 24 patients with Cushing's disease who had been given pituitary irradiation, for a median of 27 months (range 3-140) with adequate control of hypercortisolaemia in 20 (83%). In 10 patients with adrenocortical adenomas and six with adrenocortical carcinomas, metyrapone in a median dose of 1750 mg/day (range 750-6000) reduced their mean cortisol levels (median 847 nmol/l, range 408-2000) to less than 400 nmol/l in 13 patients (81%). In 18 patients with the ectopic ACTH-syndrome the 'mean cortisol levels', obtained from five or six samples on the test day (median 1023 nmol/l, range 823-6354) were reduced to less than 400 nmol/l in 13 patients (70%), on a median dose of 4000 mg/day (range 1000-6000). Reduction of cortisol levels was clearly associated with clinical and biochemical improvement. The medication was well tolerated. Transient hypoadrenalism and hirsutism were unusual but were the most common side-effects. CONCLUSIONS: In our experience metyrapone remains a most useful agent for controlling cortisol levels in the management of Cushing's syndrome of all types.

ACTH Syndrome, Ectopic↗
PubMed1985

Alteration of the inhibitory effect of metyrapone by reduction to metyrapol during the metabolism of methacetin in vivo in mice.

Metyrapone is known as an inhibitor of the oxidative drug metabolism in vitro. We have used the exhalation analysis as a tool to study the influence of this inhibitor on the demethylation of 14C-methacetin in vivo. In parallel we investigated the reductive metabolism of metyrapone in mice by measuring the concentrations of metyrapone and its reduced metabolite metyrapol with a HPLC-method. 50 mg of metyrapone/kg b. wt. resulted in a 90% inhibition of 14CO2 exhalation when given 2 min before the exhalation analysis was started. The prolongation of the intervals between i.p. metyrapone and substrate administration leads to a diminution of the in vivo inhibition. We found that the hepatic metyrapone concentration falls rapidly and passes the detection limit at 120 min. Transiently metyrapol reaches a maximal concentration 15 min after the application of metyrapone. The rapid reduction of metyrapone was confirmed in vitro with fresh mouse liver homogenates. The administration of metyrapol itself in vivo causes a decrease in 14CO2 exhalation, too. The 14CO2 exhalation curves after metyrapol correspond to the curves after metyrapone, when sufficient time was allowed for its reduction to metyrapol. It can be concluded that not only metyrapone itself but also its reductive metabolite metyrapol is an effective, however weaker inhibitor.

7-Alkoxycoumarin O-Dealkylase↗
PubMed1976

The effect of metyrapone on uterine prostaglandin output and smooth muscle activity.

Metyrapone, at low doses (0.5-1.0 mM), stimulated the output of both PGE and PGF from the isolated uterus of the pregnant rat determined following extraction of bath fluid, chromatographic separation and bioassay of the prostaglandin. At higher doses (2-4 mM), metyrapone inhibited PGF output, but had no effect on PGE output. Uterine activity was rapidly inhibited by metyrapone in a dose-related manner. This inhibition was not related to PG output as, at 1 mM metyrapone, activity was inhibited and PG output stimulated. Both metyrapone and papaverine produced dose-dependent inhibition of the activity of the isolated rabbit ileum, papaverine being 10 times more potent than metyrapone. Propranolol antagonised the response of the ileum to isoprenaline, but had no effect on the response to metyrapone. These observations confirm earlier data, suggsting that metyrapone exerts a differential effect on uterine PGE and PGF production and indicate that metyrapone has a direct inhibitory effect on smooth muscle activity.

Animals↗
PubMed1997

Metyrapone is a competitive inhibitor of 11beta-hydroxysteroid dehydrogenase type 1 reductase.

The present study was designed to examine the effects of metyrapone in vitro on the activities of 11beta-hydroxysteroid dehydrogenase (11beta-HSD) types 1 and 2, the two intracellular enzymes responsible for the metabolism of glucocorticoids. Enzymatic activities of 11beta-HSD1 and 2 were determined by a radiometric conversion assay using cortisol and cortisone as physiological substrates. The enzyme activity assays were carried out in the absence and presence of metyrapone using sheep liver and kidney microsomes as the source of 11beta-HSD1 and 2, respectively. It was found that metyrapone inhibited the reductase activity of 11beta-HSD1 in a dose-dependent manner with an apparent Ki of 30 microM. Moreover, this inhibition was competitive because the Km for cortisone was increased in the presence of metyrapone. In contrast, metyrapone showed biphasic effects on the dehydrogenase activity of 11beta-HSD1, in that it increased the activity at concentrations lower than 100 microM but decreased it at higher concentrations. However, under similar conditions, metyrapone had little effect on the unidirectional dehydrogenase activity of 11beta-HSD2. In conclusion, the present results provide the first direct evidence that metyrapone is a competitive inhibitor of 11beta-HSD1 reductase, and that it also exerts biphasic effects on 11beta-HSD1 dehydrogenase activity. These findings indicate that metyrapone influences peripheral glucocorticoid metabolism through its regulation of 11beta-HSD1 activity, in addition to its classic inhibitory effects on adrenal steroid biosynthesis. It is therefore imperative that this novel extra-adrenal effect of metyrapone be considered when this drug is used in the diagnosis and treatment of adrenocorticoid-related diseases.

11-beta-Hydroxysteroid Dehydrogenases↗
PubMed2000

The low dose ACTH stimulation test is less sensitive than the overnight metyrapone test for the diagnosis of secondary hypoadrenalism.

OBJECTIVE: The 1 microgram ACTH stimulation test has been advocated as a sensitive indicator of the integrity of the hypothalamic-pituitary-adrenal axis in patients with suspected hypopituitarism. The aim of our study was to define the normal response to 1 microgram ACTH stimulation in a control population and to study the sensitivity and specificity of the test in a group of patients with suspected pituitary disease. DESIGN: A prospective analysis of the performance of the 1 microgram ACTH stimulation test in a group of patients with pituitary disease. PATIENTS: The cortisol response to 1 microgram ACTH was evaluated in 21 normal subjects and 65 patients with pituitary disease. The patients with pituitary disease were divided into two groups according to the 11-deoxycortisol response to overnight metyrapone: normal (11-deoxycortisol > 200 nmol/l) and subnormal ACTH secretory status (11-deoxycortisol < 200 nmol/l). MEASUREMENTS: In both controls and patients, blood was sampled for cortisol at - 15, 0, + 20, + 30, + 40 and + 60 minutes after intravenous administration of 1 microgram synthetic ACTH (Synacthen(R)). The overnight metyrapone test was performed only in the subjects with pituitary disease. Metyrapone (30 mg/kg) was administered orally at 2300 h and blood was sampled at 0830 h the following morning for 11-deoxycortisol. RESULTS: The 65 patients with pituitary disease were categorized according to the 11-deoxycortisol response to metyrapone as follows: 53 normal (11-deoxycortisol > 200 nmol/l) and 12 subnormal (< 200 nmol/l). The 12 patients who failed the metyrapone test had a significantly impaired cortisol response to low dose ACTH stimulation at all time points when compared with both the control group and the pituitary patients with a normal response to metyrapone (P < 0.001). Comparing the pituitary patients who had a normal response to metyrapone and the control subjects, there was no significant difference in the cortisol response to ACTH (P > 0.05). The minimum cortisol response at 30 minutes in the 21 control subjects was 414 nmol/l and this was defined as the minimum normal cortisol response to 1 microg ACTH. Using this criterion, six of the 12 patients with a subnormal response to metyrapone had a normal cortisol response to low dose ACTH stimulation. Empirically increasing the cortisol cut-off to 600 nmol/l increased the sensitivity of the low dose ACTH test to 83%, although the specificity was reduced from 100% to only 58%. CONCLUSIONS: The normal cortisol response to low dose ACTH stimulation in 50% of the patients with ACTH deficiency proven on metyrapone testing suggests that the 1 microgram ACTH stimulation test, like the 250 microgram-test, lacks sensitivity for the diagnosis of ACTH deficiency.

Adult↗
PubMed2003

The effect of intrafetal infusion of metyrapone on arterial blood pressure and on the arterial blood pressure response to angiotensin II in the sheep fetus during late gestation.

While the impact of exogenous glucocorticoids on the fetal cardiovascular system has been well defined, relatively few studies have characterised the role of endogenous fetal glucocorticoids in the regulation of arterial blood pressure (BP) during late gestation. We have therefore infused metyrapone, an inhibitor of cortisol biosynthesis, into fetal sheep from 125 days gestation (when fetal cortisol concentrations are low) and from 137 days gestation (when fetal cortisol concentrations are increasing) and measured fetal plasma cortisol, 11-desoxycortisol and ACTH, fetal systolic, diastolic and mean arterial BP, heart rate, and the fetal BP responses to increasing doses of angiotensin II (AII). At 125 days gestation, there was a significant increase in fetal plasma ACTH and 11-desoxycortisol by 24 h after (+24 h) the start of the metyrapone infusion, and plasma cortisol concentrations were not different at +24 h when compared with pre-infusion values. Whilst the initial fall in circulating cortisol concentrations may have been transient, systolic, diastolic and mean arterial BP were ~5-6 mmHg lower (P < 0.05) in metyrapone- than in vehicle-infused fetuses at 24-48 h after the start of the infusion. When metyrapone was infused from 137/138 days gestation, there was a significant decrease in plasma cortisol concentrations by +6 h, which was followed by an increase back to pre-infusion values. While cortisol concentrations decreased, there was no change in fetal mean arterial BP during the first 24 h after the start of metyrapone infusion. Mean fetal arterial BP values at 137-139 days gestation were not different in fetuses that had been infused with either vehicle or metyrapone from 125 days gestation or with metyrapone from 137/138 days gestation. At 137-139 days gestation, however, arterial BP responses to increasing doses of AII were significantly blunted in fetuses that had been infused with metyrapone from 125 days gestation, when compared with fetuses that had been infused with metyrapone from 137/138 days gestation or with vehicle from 125 days gestation. The dissociation of the gestational age increase in arterial BP and the effects of intrafetal AII on fetal arterial BP indicates that increase in fetal BP with gestational age is not entirely a result of an increased vascular responsiveness to endogenous AII. Furthermore there may be a critical window during late gestation when the actions of cortisol contribute to the development of vascular responsiveness to AII.

Adrenocorticotropic Hormone↗
PubMed2005

Effect of combined treatment with imipramine and metyrapone on the immobility time, the activity of hypothalamo-pituitary-adrenocortical axis and immunological parameters in the forced swimming test in the rat.

Major depression is frequently associated with the hyperactivity of the hypothalamic-pituitary-adrenocortical axis, and glucocorticoid synthesis inhibitors have been shown to exert antidepressant action. The aim of the present study was to examine the effect of joint administration of metyrapone (50 mg/kg) and imipramine (5 and/or 10 mg/kg) on immobility time, plasma corticosterone concentration, the weight of spleens and thymuses and the proliferative activity of splenocytes in rats subjected to the forced swimming test--an animal model of depression. Metyrapone alone (50 mg/kg) reduced the immobility time of rats in the forced swimming test and decreased plasma corticosterone level, but did not change immunological parameters. Joint administration of metyrapone and imipramine (5 and 10 mg/kg) produced a more pronounced antidepressant-like effect than either of the drugs given alone. The forced swimming procedure significantly increased the proliferative activity of splenocytes, that parameter being reduced only by co-administration of metyrapone and imipramine. Joint administration of metyrapone and imipramine inhibited to a similar extend the corticosterone level as did treatment with metyrapone alone (about twofold); however, the plasma corticosterone level in animals treated with metyrapone and the higher dose of imipramine did not differ from the concentration of this steroid in control, not-stressed rats. The obtained results indicate that metyrapone potentiates the antidepressant-like activity of imipramine and exerts a beneficial effect on the stress-induced increase in plasma corticosterone concentration and the proliferative activity of splenocytes. These finding suggest that a combination of metyrapone and an antidepressant drug may be useful for the treatment drug-resistant depression and/or depression associated with a high cortisol level.

Animals↗
PubMedDate not supplied

Impact of metyrapone on MK-801-induced alterations in the rat dopamine D1 receptors.

Our earlier studies have shown that changes in serum corticosterone levels played an important role in the acquisition of sensitization to MK-801, a non-competitive NMDA receptor antagonist. Dopaminergic mechanisms are found to be particularly important in the development of sensitization; hence in the present study we assessed the binding of [3H]SCH 23390 at brain dopaminergic D1 receptors, after administration of MK-801 (0.4 mg/kg), in rats in which corticosterone synthesis was inhibited by metyrapone (150 + 50 mg/kg). Such metyrapone pretreatment prevented the increases in serum corticosterone level induced by MK-801. The binding studies, using receptor autoradiography, were performed in the following brain structures: the striatum, nucleus accumbens, olfactory tubercle and substantia nigra. Metyrapone per se did not change or slightly increased D1 receptor binding in the substantia nigra, while in other brain structures tested it decreased the number of these receptors by about 30%. MK-801 increased the level of D1 receptors in the nucleus accumbens core and olfactory tubercle, being without effect in the remaining brain structures tested. In rats which were pretreated with metyrapone, the effect of MK-801 on D1 receptors was inhibited in the nucleus accumbens core only. In substantia nigra, metyrapone provoked the MK-801-induced decrease in D1 receptors whereas in all other structures MK-801 reversed the effects of metyrapone on D1 receptors. Additionally, the effect of metyrapone and MK-801 on grooming behavior induced by D1 receptor agonist SKF 38393 (10 mg/kg) was tested. Metyrapone did not influence grooming induced by SKF 38393, but significantly potentiated the inhibitory effect of MK-801 on this behavior. Finally, we found that metyrapone did not influence the expression of the sensitization induced by MK-801. Our results seem not to support hypothesis that MK-801 evokes enhancement of dopaminergic neurotransmission (at the level of D1 receptors) via corticosterone liberation, since in most brain regions studied inhibition of increases in corticosterone level did not prevent MK-801-induced effects on D1 receptors. The present study may suggest that NMDA receptors are involved in the corticosterone-dependent regulation of the density of the D1 receptors.

2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-ben↗
PubMed1982

Binding of metyrapone to dithionite-reduced cytochrome P-450 from rats treated with xenobiotics.

The in vitro binding of metyrapone to dithionite-reduced cytochrome P-450 in hepatic microsomes from rats treated in vivo with thirteen different xenobiotics was studied spectrophotometrically. The proportion of cytochrome P-450 that bound metyrapone increased 1.8-fold to about 78% following treatment with phenobarbitone (PB) and PB-type inducers (trans-stilbene oxide, 2,2',4,4'-tetrachloro-, 2,2',4,5,5'-pentabromo- and 2,2',4,4',5,5'-hexachlorobiphenyl) but remained unaltered following treatment with 3-methylcholanthrene (MC) and MC-type induces (benzo[a]pyrene, beta-naphthoflavone and 3,3',4,4'-tetrabromobiphenyl). The simultaneous induction of the PB-inducible and MC-inducible forms of cytochrome P-450 by administering Aroclor 1254 or by coadministering PB with MC increased the proportion of cytochrome P-450 that bound metyrapone to 74 and 78% respectively. PB treatment increased whereas MC treatment decrease the binding affinity for metyrapone by approximately 20-fold. Treatment with isosafrole or metyrapone itself failed to stimulate metyrapone binding. In contrast, pregnenolone-16 alpha-carbonitrile was indistinguishable from PB in its ability to increase the binding capacity and binding affinity for metyrapone. Our results indicate that metyrapone binding is not specific for cytochrome P-450b, the major PB-inducible hemoprotein, as has been proposed [V. Luu-The, J. Cumps and P. Dumont, Biochem. biophys. Res. Commun. 93, 776 (1980)].

Animals↗
PubMed1994

Effect of metyrapone on tryptophan binding to rat hepatic nuclei.

This study evaluated whether metyrapone (2-methyl-1,2-di-3-pyridyl-1-propanone), an inhibitor of endogenous adrenal corticosteroid synthesis via inhibition of cytochrome P-450-mediated steroid hydroxylation, would influence the binding of L-tryptophan to rat hepatic nuclei or nuclear envelopes. Previous publications have indicated that binding of L-tryptophan to hepatic nuclear envelope proteins was saturable, stereospecific, and of high affinity. In this study, we investigated whether metyrapone would influence L-tryptophan binding to rat hepatic nuclei or nuclear envelopes as assayed by in vitro L-(5-3H)tryptophan binding. Our results indicate that the addition of metyrapone in vitro has little influence on L-(5-3H)tryptophan binding to hepatic nuclei or nuclear envelopes. On the other hand, when metyrapone (1 mg/100 g body weight) is tube-fed 30 minutes before killing, the isolated hepatic nuclei show decreased specific L-tryptophan binding (total binding minus nonspecific binding [using 2,000-fold excess of unlabeled L-tryptophan]) compared with controls. Also, addition of metyrapone in vitro to rat liver before homogenization and preparation of nuclei caused the nuclei to show decreased specific tryptophan binding compared with controls. Under these in vitro conditions, SKF 525A, another inhibitor of hydroxylation, showed inhibitory effects similar to those of metyrapone. Thus, metyrapone can interfere with rat liver nuclear envelope receptor binding to L-tryptophan, and possibly acts via its effects on hydroxylation. At high doses, metyrapone (20 mg/100 g body weight) appears to inhibit tryptophan-induced stimulation of hepatic protein synthesis.

Animals↗
PubMed2004

Behavioral effects of metyrapone on Pavlovian extinction.

This is the first study of the action of metyrapone on Pavlovian extinction. Pavlovian acquisition memory can be impaired when 50 mg/kg metyrapone, a corticosterone synthesis inhibitor, is injected 90 min before training. It was hypothesized that the same treatment given before extinction may also impair Pavlovian extinction memory, and thereby facilitate recovery of the extinguished behavior. This study examined the behavioral effects of 50 mg/kg metyrapone on the extinction of conditioned freezing following Pavlovian conditioning of tone (CS) and footshock (US). On days 1-2, mice were habituated to the training context. On days 4-5, mice received 4 tone-shock pairings per day. On day 6, metyrapone or saline was injected s.c. 90 min before an extinction session with 60 tone presentations. Probe sessions with 4 tones were conducted in the extinction context on day 7 and in the acquisition context on day 9. Metyrapone treatment did not affect performance during extinction or pre-CS freezing behavior. But metyrapone-treated animals showed greater conditioned freezing when tested with the tone the day after extinction in the extinction context (spontaneous recovery) and 3 days after extinction in the acquisition context (renewal effect). It was concluded that 50 mg/kg metyrapone did not affect extinction performance, but it effectively facilitated the subsequent recovery of the extinguished behavior. This effect may be explained by an impairment of the consolidation of the Pavlovian extinction memory. This interpretation is consistent with previous studies showing that metyrapone may interfere with memory consolidation for a variety of learned responses.

Animals↗
PubMed1997

Postoperative metyrapone test in the early assessment of outcome of pituitary surgery for Cushing's disease.

OBJECTIVE: The prediction of relapse during the early months after transsphenoidal surgery for Cushing's disease remains difficult. We have evaluated the usefulness of the postoperative metyrapone test in this situation. PATIENTS: From a retrospective series of 77 consecutive primary pituitary operations for Cushing's disease 29 patients, who also had a metyrapone test at 14 days postoperatively, were selected. Median follow-up was 35 months (range: 8-118 months). MAIN OUTCOME MEASURES: Early postoperative: fasting morning serum cortisol, 24-hour urinary cortisol excretion, serum 11-deoxycortisol after 6 x 750 mg metyrapone. Remission was defined as a fasting morning serum cortisol < 140 nmol/l and/or 24-hour urinary cortisol excretion < 250 nmol. During follow-up: serum cortisol, as well as serum cortisol in the 1 mg overnight dexamethasone-suppression test was measured in order to detect relapse of Cushing's disease. RESULTS: Twelve of 29 patients were not in remission after surgery. These patients all had serum 11-deoxycortisol levels > 350 nmol/l after metyrapone. Seventeen patients met the criteria for early remission. Four of these patients had serum 11-deoxycortisol levels between 150 nmol/l and 350 nmol/l after metyrapone. Three of these 4 patient's experienced a relapse of Cushing's disease during follow-up. In the 13 patients with a serum 11-deoxycortisol < 150 nmol/l after metyrapone, no relapse occurred. CONCLUSIONS: The metyrapone test is a useful test in the assessment of outcome of pituitary surgery for Cushing's disease, with a sensitivity of 100% and a specificity of 75% for the early detection of patients at risk of a relapse. Patients in whom a serum 11-deoxycortisol > 150 nmol/L is found after metyrapone are at a high risk for relapse of Cushing's disease.

Adolescent↗
PubMed2002

Evidence that metyrapone can act as a stressor: effect on pituitary-adrenal hormones, plasma glucose and brain c-fos induction.

Metyrapone, a 11-beta steroid hydroxylase inhibitor that blocks stress-induced glucocorticoid release, is extensively used to study the physiological and behavioural roles of glucocorticoids. However, there is circumstantial evidence suggesting that metyrapone could act as a pharmacological stressor. Thus, the effects of various doses of metyrapone on two well-characterized stress markers (ACTH and glucose) were studied in male rats. Metyrapone administration, while exerting a modest effect on plasma corticosterone levels, dose-dependently increased plasma ACTH and glucose levels. Using the highest doses previously tested (200 mg/kg) we further observed, as evaluated by fos-like immunoreactivity (FLI), a strong activation of a wide range of brain areas, including the parvocellular region of the hypothalamic paraventricular nucleus (PVNp), the origin of the main ACTH secretagogues. Metyrapone-induced FLI was observed in neocortical and allocortical areas, in several limbic, thalamic and hypothalamic nuclei and, to a lesser extent, in the brainstem. In a final experiment, a dose-response study of metyrapone-induced FLI was carried out focusing on selected brain areas. The study revealed that the paraventricular thalamic nucleus and central amygdala were the areas most sensitive to metyrapone as they responded even to the lowest dose of the drug. Most areas, among them the PVNp, only showed enhanced FLI with the two highest doses, i.e. when it was associated with ACTH and glucose responses. These data suggest that some of the effects of metyrapone could be due to its stressful properties rather than its ability to inhibit glucocorticoid synthesis. The exact mechanisms involved remain to be established.

Adrenocorticotropic Hormone↗
PubMed1994

Pituitary function tests: comparison of ACTH and 11-deoxy-cortisol responses in the metyrapone test and with the insulin hypoglycemia test.

PURPOSE: To compare the sensitivity of ACTH and 11-deoxy-cortisol (comp. S) responses in the short metyrapone test and the latter with the insulin hypoglycemia test. METHODS: Retrospective evaluation of 115 short metyrapone tests and comparison of 18 pairs of metyrapone and insulin tests. 20 healthy controls and 95 patients with confirmed pituitary disease were studied. All hormones were measured by sensitive radioimmunoassays. RESULTS: In patients with pituitary disease not requiring hydrocortisone substitution (n = 70), the ACTH response in the metyrapone test was subnormal in 47 cases (< 33 pmol/L), the comp. S response (< 200 nmol/L) in 21 cases only. Comparison of the relationship between ACTH and comp. S with an ACTH-cortisol dose-response curve obtained in normal subjects shows that subnormal ACTH responses after metyrapone in the range between 13 and 33 pmol/L still generate normal comp. S responses. The results of the metyrapone test correlated significantly with those of the insulin test. CONCLUSIONS: Measuring plasma ACTH in the scope of the metyrapone test makes the test more sensitive to detect secondary adrenal insufficiency than with steroid measurements alone. Results of the metyrapone test correlate significantly with the cortisol response to insulin hypoglycemia.

Adrenocorticotropic Hormone↗