ABSTRACT
Cortisol availability is modulated by several enzymes: 11ß-HSD2, which transforms cortisol (F) to cortisone (E) and 11ß-HSD1 which predominantly converts inactive E to active F. Additionally, the A-ring reductases (5α- and 5ß-reductase) inactivate cortisol (together with 3α-HSD) to tetrahydrometabolites: 5αTHF, 5ßTHF, and THE. The aim was to assess 11ß-HSD2, 11ß-HSD1, and 5ß-reductase activity in hypertensive patients. Free urinary F, E, THF, and THE were measured by HPLC-MS/MS in 102 essential hypertensive patients and 18 normotensive controls. 11ß-HSD2 enzyme activity was estimated by the F/E ratio, the activity of 11ß-HSD1 in compare to 11ß-HSD2 was inferred by the (5αTHF + 5ßTHF)/THE ratio and 5ß-reductase activity assessed using the E/THE ratio. Activity was considered altered when respective ratios exceeded the maximum value observed in the normotensive controls. A 15.7% of patients presented high F/E ratio suggesting a deficit of 11ß-HSD2 activity. Of the remaining 86 hypertensive patients, two possessed high (5αTHF + 5ßTHF)/THE ratios and 12.8% had high E/THE ratios. We observed a high percentage of alterations in cortisol metabolism at pre-receptor level in hypertensive patients, previously misclassified as essential. 11ß-HSD2 and 5ß-reductase decreased activity and imbalance of 11ß-HSDs should be considered in the future management of hypertensive patients.
Subject(s)
11-beta-Hydroxysteroid Dehydrogenase Type 2/metabolism , 17-Hydroxycorticosteroids/urine , Hypertension/enzymology , Hypertension/urine , Oxidoreductases/metabolism , 11-beta-Hydroxysteroid Dehydrogenase Type 1/metabolism , 17-Hydroxycorticosteroids/chemistry , 3-alpha-Hydroxysteroid Dehydrogenase (B-Specific)/metabolism , Adult , Algorithms , Chile , Chromatography, High Pressure Liquid , Cortisone/chemistry , Cortisone/urine , Female , Humans , Hydrocortisone/chemistry , Hydrocortisone/urine , Hypertension/classification , Male , Middle Aged , Mineralocorticoid Excess Syndrome, Apparent/diagnosis , Mineralocorticoid Excess Syndrome, Apparent/enzymology , Mineralocorticoid Excess Syndrome, Apparent/urine , Tandem Mass Spectrometry , Tetrahydrocortisol/chemistry , Tetrahydrocortisol/urine , Tetrahydrocortisone/chemistry , Tetrahydrocortisone/urineABSTRACT
Hydrocortisone, cortexolone, hydrocortisone-17-butyrate, and budesonide were oxidized into alpha-ketoaldehydes by air exposure in the presence of Cu(OAc)(2). When free hydroxyl functions were present at position 17, hydrocortisone and cortexolone, the formed oxidation products, were identified as hemiacetal dimeric structures involving the free hydroxyl functions at position 17 and the newly formed aldehydes at position 21. Dimeric structures were established by using 1H913C0 correlations (HSQC and HMBC) and 1H-1H correlations (COSY and ROESY). The hemiacetal function was further confirmed by reaction of the dimer formed from hydrocortisone with two equivalents of 3-methyl-2-benzotriazolinone hydrazine (MTBH), giving quantitatively two equivalents of the 3-methyl-2-benzotriazolinone hydrazone of 21-dehydrohydrocortisone. When no free hydroxyl function was present as in the case of hydrocortisone-17-butyrate and budesonide, the expected alpha-ketoaldehydes were obtained.
Subject(s)
17-Hydroxycorticosteroids/chemistry , Acetals/chemistry , Organometallic Compounds/metabolism , 17-Hydroxycorticosteroids/metabolism , Acetals/isolation & purification , Air , Aldehydes/chemistry , Aldehydes/isolation & purification , Catalysis , Dimerization , Nuclear Magnetic Resonance, Biomolecular , Oxidation-ReductionABSTRACT
A facile and convenient approach to 17-ketosteroids is described. Treatment of steroids containing the C-17-dihydroxy acetone side chain with an excess of sodium methoxide in dry 1,4-dioxane under reflux, affords high yields of the corresponding 17-ketosteroids that are recovered as pure products, without the need of further purification.
Subject(s)
17-Hydroxycorticosteroids/chemistry , 17-Ketosteroids/chemical synthesis , Acetone/chemistry , 17-Ketosteroids/chemistry , Molecular StructureABSTRACT
Five corticosteroids were tested to determine whether they are able to overcome the multidrug resistance of vincristine resistant mouse leukemia cells L1210/VCR. The most effective in reversing multidrug resistance were cortisone and dexamethasone, less effective as reversing agents were 11-deoxycorticosterone, 1-dehydrocortisone and hydrocortisone. By testing of collateral sensitivity of vincristine resistant cell line to these corticosteroids it was found that only 11-deoxycorticosterone and dexamethasone were toxic to multidrug resistant cells at doses much lower than required for toxicity to the drug-sensitive L1210/S cells. Using thin layer chromatography the polarity of tested corticosteroids was estimated, and good correlation was found between polarity of corticosteroids and their increased toxicity to vincristine resistant cells.
