Cortisol metabolism by human liver in vitro—IV. Metabolism of 9α-fluorocortisol by human liver microsomes and cytosol

The oxidative and reductive biotransformations of 9α-fluorocortisol (fluorocortisol) by human liver microsomes and cytosol have been characterized. 9α-Fluorination greatly simplified cortisol metabolism in microsomes: dehydrogenation of the 11β-hydroxyl group and A-ring (4-ene-5β and 3α-keto) reduction, the principle pathways, were completely blocked. Fluorocortisol was essentially metabolized by the remaining pathways, 20β-reduction and 6β-hydroxylation. In cytosol, 20β-reduction replaced the A-ring reduction of cortisol as the sole biotransformation. The major structure-metabolism relationships of fluorocortisol in man, i.e. complete and extensive inhibition of 11β-dehydrogenation and 4-ene-5β-reduction, respectively, were attributed to hepatic enzyme systems. Their mechanistic basis is discussed with reference to the electronic and conformational changes induced by 9α-fluorination.