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The metabolism of 9α-fluorinated steroids in the human kidney

1996; Taylor & Francis; Volume: 22; Issue: 4 Linguagem: Inglês

10.1080/07435809609043779

1532-4206

Sven Diederich, B. Hanke, V. Bähr, W. Oelkers,

Eicosanoids and Hypertension Pharmacology

We compared the renal metabolism of 9α-fluorinated steroids with that of the unfluorinated, endogenous steroid cortisol (F) By defining kinetic variables, we characterized isoenzyme activities of 11ß-hydroxysteroid-dehydrogenase (11ß-HSD). Methods: I) In human kidney slices, we studied the conversion of 9α-fluoro-cortisol (FF) and F to their oxo-products (and vice versa). II) In human kidney microsomes, we performed the kinetic analysis of 11ß-HSD activity for the steroid pairs F/cortisone (E) and dexamethasone (D)/11-dehydro-dexamethasone (DH-D). Results: I) In kidney slices, FF is very weakly oxidized to 9α-fluorocortisone (FE), while the reduction of FE to FF is very effective. In contrast, E is hardly reduced to F, but F is strongly inactivated to E. II) Enzyme kinetics in kidney microsomes: 1a) Oxidation of F to E: exclusively NAD-dependent; Km = 25.5 nmol/L. b) Reduction of E to F: clearly NADH-preferring; Km = 81 nmol/L; Vmaxoxidation/Vmaxreduction (F/E) = 26. 2a) Oxidation of D to DH-D: exclusively NAD-dependent; Km = 81 nmol/L b) Reduction of DH-D to D: exclusively NADH-dependent; Km = 68 nmol/L; Vmaxoxidation /Vmaxreduction (D/DH-D) = 0.09. Thus, the equilibrium of FF/FE in human kidney slices is far on the biologically active hydroxy-side. This shift, induced by the 9-fluorination, gives a good explanation for its mineralocorticoid potency. The cosubstrate dependence and the Km-value of the oxidation of F are similar to these of the cloned human 11ß-HSD-II. For the first time, we could show a NADH-dependent reduction of E to F. Moreover, we found that the preference of D/DH-D for the reductase reaction (see the quotients Vmaxoxidation/Vmaxreduction) is due to a NADH-dependent enzyme (probably 11ß-HSD-II). These results provide strong evidence against the “dogma” of an “unidirectional” 11ß-HSD-II.