The 11β-hydroxysteroid dehydrogenase isoforms: pivotal catalytic activities yield potent C11-oxy C19 steroids with 11βHSD2 favouring 11-ketotestosterone, 11-ketoandrostenedione and 11-ketoprogesterone biosynthesis

Abstract

The 11β-hydroxysteroid dehydrogenase (11βHSD) types 1 and 2 are primarily associated with glucocorticoid inactivation and reactivation. Several adrenal C11-oxy C₁₉ and C11-oxy C₂₁ steroids, which have been identified in prostate cancer, 21-hydroxylase deficiency and polycystic ovary syndrome, are substrates for these isozymes. This study describes the kinetic parameters of 11βHSD1 and 11βHSD2 towards the C11-keto and C11-hydroxy derivatives of the C₁₉ and C₂₁ steroids. The apparent K_m and V_max values indicate the more prominent 11βHSD2 activity towards 11β-hydroxy androstenedione, 11β-hydroxytestosterone and 11β-hydroxyprogesterone in contrast to the 11βHSD1 reduction of the C11-keto steroids, as was demonstrated in the LNCaP cell model in the production of 11-ketotestosterone and 11-ketodihydrotestosterone. Data highlighted the role of 11βHSD2 and cytochrome P450 17A1 in the contribution of C11-oxy C₂₁ steroids to the C11-oxy C₁₉ steroid pool in the C11-oxy backdoor pathway. In addition, 11βHSD2 activity, catalysing 11-ketotestosterone biosynthesis, was shown to be key in the production of prostate specific antigen and in the progression of prostate cancer to castration resistant prostate cancer. The study at hand thus provides evidence that 11βHSD isozymes play key roles in pathophysiological states, more so than was previously put forward.

Keywords: 11β-hydroxysteroid dehydrogenase (11βHSD); 21-hydroxylase deficiency (21OHD, 21-OH CAH); Adrenal 11β-hydroxyandrostenedione (11OHA4, 11OHAD); Castration resistant prostate cancer (CRPC); Cortisol; Cortisone; Cytochrome P450 17α-hydroxylase/17,20-lyase (CYP17A1); Polycystic ovary syndrome (PCOS).