Glucocorticoids are the most effective anti -inflammatory agents currently available, but a variety of adverse effects limit their clinical usefulness. This work explores further two facets of the interaction between glucocorticoids and the skin, with the aim of identifying means of reducing glucocorticoid toxicity.(a) Metabolism of glucocorticoids by skin: Human skin is active in the terminal metabolism of cortisol to cortisone, but the biological implications of this process in skin are uncertain. Because there are technical difficulties in dealing with human skin, an animal model, the nude mouse, has been evaluated for its suitability to the study of the metabolism of corticosterone to 11B- dehydrocorticosterone (the homologous reaction in rodents of cortisol to cortisone conversion in man); a process mediated by 1 l ß- hydroxysteroid dehydrogenase. The skin of the nude mouse has previously been shown to be appropriate for pharmacokinetic and phannacodynamic studies of glucocorticoids. In this model, skin 11B- hydroxysteroid dehydrogenase had an apparent Km for corticosterone of 37 p.M. Skin 11B- hydroxysteroid dehydrogenase was up- regulated, in -vivo, by active glucocorticoids and was NADP dependent. By comparison, kidney 1 Iß- hydroxysteroid dehydrogenasé had a higher apparent Km (120 μM) for corticosterone, used NAD and NADP with equal facility and was not regulated in- vivo by glucocorticoids. These data suggest that the skin may possess an isoform distinct from that of the kidney. Immunohistochemical studies demonstrated that 11ß -hydroxysteroid dehydrogenase was most abundant in the epidermis. In- vitro, this enzyme was markedly inhibited by glycyrrhetinic acid, the active principle in liquorice. Using the classic bioassay of glucocorticoid activity (skin vasoconstrictor assay), it was found that co- application of glycyrrhetinic acid and hydrocortisone resulted in potentiation of skin vasoconstrictor activity of hydrocortisone. This suggests that inhibition of hydrocortisone metabolism might explain the long recognised but poorly understood anti - inflammatory action of liquorice and its congeners and may represent a novel means of targeting glucocorticoid therapy.(b) Skin vasoconstrictor response (blanching) to topical glucocorticoids: Glucocorticoids applied topically to human skin produce vasoconstriction in dermal vessels, the degree of which correlates closely with the potency and clinically efficacy of these compounds. Although previous workers had noted heterogeneity in blanching responses to glucocorticoids, this was never systematically studied. In qualitative studies, it was shown that skin blanching was inducible by RU- 28362, a specific glucocorticoid receptor (type II) agonist and blocked by RU- 38486, a glucocorticoid antagonist. Moreover, aldosterone (type I receptor agonist) failed to produce blanching. In addition blanching was observed in an individual with clinical and biochemical features of aldosterone receptor deficiency. These data therefore suggest that blanching is a glucocorticoid specific phenomenon mediated via the classical glucocorticoid receptor. To test whether skin vasoconstrictor response might reflect glucocorticoid sensitivity, blanching responses was tested in a clinical model of glucocorticoid resistance. In patients with glucocorticoid resistant asthma, skin responsiveness was also found to be diminished. Responsiveness was also somewhat diminished in a cohort of asthmatics on long term prednisolone. Skin vasoconstrictor responsiveness might therefore reflect systemic sensitivity to glucocorticoids and previous glucocorticoid use might reduce skin responsiveness. When tested against other parameter indicating systemic glucocorticoid effects, acute systemic glucocorticoid exposure over 10 days did not affect skin responsiveness. It is possible that resistance to the anti -inflammatory effects of glucocorticoids might accrue from long term exposure and it might therefore be possible to use the skin vasoconstrictor assay a marker for glucocorticoid sensitivity - a novel purpose for this long used assay
