Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P01189 (beta-endorphin)
 21,003 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The involvement of endogenous benzodiazepine octadecaneuropeptide in the regulation of corticotropin-releasing hormone messenger RNA expression has been studied using in situ hybridization technique. Intracerebroventricular injection of octadecaneuropeptide (4 microg/kg) induced a 26% decrease in the corticotropin-releasing hormone messenger RNA expression in the hypothalamic paraventricular nucleus. Concomitant injection of octadecaneuropeptide and i.p. injection of the GABA(A) receptor agonist muscimol (4 mg/kg) potentiated the corticotropin-releasing hormone messenger RNA decrease ( - 34%). The depressing effect of octadecaneuropeptide on corticotropin-releasing hormone gene expression was totally reversed by pretreatment of the animals with the GABA(A) receptor antagonist picrotoxin (5 mg/kg; i.p.) or by pretreatment with the benzodiazepine receptor antagonist flumazenil (4 mg/kg; i.p.). To determine the reciprocal involvement of adrenal and sexual steroids in this regulation, animals are adrenalectomized and/or castrated. Adrenalectomy reversed the effect induced by octadecaneuropeptide, which increased corticotropin-releasing hormone messenger RNA expression (+21%), while castration did not modify the negative influence of octadecaneuropeptide. When rats were adrenalectomized and castrated, the adrenalectomy influence was predominant, since octadecaneuropeptide increased significantly the hybridization signal (+18%). The involvement of neurosteroids, especially reduced metabolites of progesterone was also investigated. The concomitant injection of octadecaneuropeptide and subcutaneous injection of the 5alpha-reductase inhibitor MK-906 (14 mg/kg) to adrenalectomized and castrated rats, reduced significantly by 60% the increase of corticotropin-releasing hormone messenger RNA expression induced by octadecaneuropeptide. These results indicate that in vivo the endogenous benzodiazepine octadecaneuropeptide, via an activation of the benzodiazepine sites of the GABA(A) receptor, negatively modulates corticotropin-releasing hormone neuronal activity and that this modulation can be negatively or positively influenced by central and peripheral steroids.
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PMID:The octadecaneuropeptide-induced response of corticotropin-releasing hormone messenger RNA levels is mediated by GABA(A) receptors and modulated by endogenous steroids. 962 52

To continue our studies on the cutaneous expression of a proopiomelanocortin/corticotropin-releasing hormone system, we investigated whether this is accompanied by adrenal-type enzymatic activity. Immortalized cultured human keratinocytes were incubated with radiolabeled corticosteroids. Analysis by thin-layer chromatography showed rapid transformation of both progesterone and deoxycorticosterone; one of the progesterone metabolites migrated at the same rate as deoxycorticosterone. Gas chromatography/mass spectrometry further identified as major species of deoxycorticosterone metabolites 3beta,6alpha,21-trihydroxy-5alpha-pregnan-20-one, 3alpha,6alpha,21-trihydroxy-5alpha-pregnan-20-one, and 3alpha5alpha- and 3beta5alpha-tetrahydrodeoxycorticosterone. Minor metabolites were 3alpha,21-dihydroxy-5-pregnen-20- one (3alphaDelta5-21-OHpregnenolone), 3beta,21-dihydroxy-5-pregnen-20-one (3betaDelta5-21-OHpregnenolone), 3alpha,21-dihydroxy-4-pregnen-20-one (3alphaDelta4-21-OHpregnenolone), 6-hydroxy-dihydrodeoxycorticosterone, and two 5-dihydrodeoxycorticosterone species. Thus, in addition to sex steroids keratinocytes also actively metabolize corticosteroids along similar enzymatic pathways. The surprising detection of 3alphaDelta5-21-OHpregnenolone and 3 betaDelta5-21-OHpregnenolone, indicating Delta4-ketosteroids to Delta5-hydroxysteroids conversion, provides strong evidence for the occurrence, at least in human keratinocytes, of isomerase activity that allows the reaction to proceed in reverse of its usual direction. As skin expresses 3alpha/beta-hydroxysteroid dehydrogenase/Delta5-Delta4 isomerases, cutaneous reactions catalyzed by these enzymes must be reversible. In conclusion, besides elements of the corticotropin-releasing hormone/proopiomelanocortin system human keratinocytes show high levels of corticosteroid metabolizing activity. Moreover, the wide array of steroid products generated from a single substrate indicates serial progressive conversion involving 5alpha-reductase, 6alpha-hydroxylase, 3alpha/beta-hydroxysteroid dehydrogenase, and reverse Delta4minus signDelta5 isomerase enzymes. As distinct from the adrenal cortex, production of A, B, Aldo, 18OHdeoxycorticosterone, or F in keratinocytes was absent or below limits of detectability.
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PMID:Gas chromatography/mass spectrometry characterization of corticosteroid metabolism in human immortalized keratinocytes. 1184 49

In diabetes, dysregulation of the hypothalamic-pituitary-adrenocortical (HPA) axis causes effects such as elevation of corticotropin (ACTH) and glucocorticoids. Cholecystokinin and its receptors are involved in the HPA axis and influence the regulation of the HPA axis. We examined adrenocortical function in Otsuka Long-Evans Tokushima Fatty (OLETF) rats, a model of type 2 diabetes mellitus, that lack the cholecystokinin A receptor. We measured adrenal weight, plasma ACTH, serum and urinary corticosterone, and serum leptin in OLETF rats at 5 to 36 weeks of age. Messenger RNA (mRNA) expression of 11beta-hydroxysteroid dehydrogenase and 5alpha-reductase type 1 in adrenal glands of the rats were examined. Long-Evans Tokushima Otsuka (LETO) rats were used as controls. In OLETF rats at 32 to 36 weeks of age, plasma ACTH was significantly higher (P < .001); serum corticosterone and 24-hour urinary corticosterone were significantly lower (P < .005); and adrenal weight was significantly lower (P < .005) than those in LETO rats. At the same ages, serum leptin in OLETF rats was significantly higher (P < .001) than that in LETO rats. In the younger OLETF rats, these changes were not observed. Overall, there was an inverse correlation between serum corticosterone and serum leptin (r = -0.374, P < .0005), whereas there was a positive correlation between plasma ACTH and serum leptin (r = 0.654, P < .0001). At 5 and 36 weeks of age, mRNA expression of 5alpha-reductase type 1 in the adrenal gland of OLETF rats was significantly higher (P < .05) than that of LETO rats, whereas there was no significant difference in mRNA expressions of 11beta-hydroxysteroid dehydrogenase types 1 and 2. We showed that adrenocortical insufficiency and adrenal atrophy were acquired in OLETF rats, and the possibility of elevated serum leptin relates to this phenomenon.
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PMID:Adrenocortical insufficiency in Otsuka Long-Evans Tokushima Fatty rats, a type 2 diabetes mellitus model. 1788 40