Glucocorticoid (GC) hormone action can be modulated at the pre-receptor level by the endoluminal enzyme 11β-hydroxysteroid dehydrogenase type 1 (11βHSD1). 11βHSD1 is a bidirectional enzyme that primarily acts as an oxo-reductase in vivo, converting the pro-hormone cortisone to its active form cortisol, while its dehydrogenase activity results in inactivation of cortisol to cortisone. 11βHSD1 oxo-reductase activity allows GC reactivation in a tissue specific manner and thereby amplification of GC effects in the peripheral target cell. Pre-receptor regulation of steroid hormone action crucially depends on the intra-cellular availability of co-factor and the critical driver of 11βHSD1 oxo-reductase activity is the local availability of NADPH. The novel congenital adrenal hyperplasia variant apparent cortisone reductase deficiency (ACRD) has highlighted the significance of this. In ACRD, 11βHSD1 oxo-reductase activity is absent, which leads to a diminished glucocorticoid feedback to the pituitary, yielding an increased ACTH release and subsequently increased adrenal androgen production. This leads to pseudo-precocious puberty in children while the adult phenotype resembles polycystic ovary syndrome. We have recently shown that loss of 11βHSD1 oxo-reductase activity can be due to mutations in the NADPH-regenerating enzyme hexose-6-phosphate dehydrogenase (H6PDH). H6PDH is located in the lumen of the endoplasmic reticulum (ER) and utilises glucose-6-phosphate and NADP as co-substrates to generate NADPH. The recently generated H6PDH mouse knockout model provides further evidence for the crucial role of H6PDH in the regulation of 11βHSD1 oxoreductase activity. Deletion of H6PDH results in a switch in enzyme directionality: rather than functioning as oxo-reductase 11βHSD1 becomes a potent dehydrogenase inactivating cortisol to cortisone. ACRD is a fascinating human experiment of nature that paradigmatically highlights the critical contribution of redox potential regulation to the pre-receptor regulation of glucocorticoids.
06 - 07 Nov 2006
Society for Endocrinology