Co-evolution of steroidogenic and steroid-inactivating enzymes and adrenal and sex steroid receptors

Abstract

Receptors for the adrenal and sex steroids arose by a series of gene duplications from an ancestral nuclear receptor in a primitive vertebrate, at least 540 million years ago. Sequence analysis indicates many steroidogenic and steroid-inactivating enzymes, including cytochrome P450s and hydroxysteroid dehydrogenases (HSDs), arose at the same time. The estrogen receptor (ER) appears to be the ancestral steroid receptor. Initially, the redundant duplicated ER had a low specificity for its new ligand. This raises the question: “How was specificity for responses to different steroids regulated early in the evolution of steroid receptors?” Selective expression of these steroid-metabolizing enzymes provided specificity for different steroid responses in primitive vertebrates. 17β-Hydroxysteroid dehydrogenase-type 1 (17β-HSD-type 1) and 17β-HSD-type 2, which preferentially catalyze the reduction and oxidation at C17 of androgens and estrogens, respectively, provide an example of this mechanism. Selective expression of either 17β-HSD-type 1 or 17β-HSD-type 2 can regulate synthesis or inactivation of androgens or estrogens in specific cells. Steroids also were important in the evolution of land animals, which began about 400 million years ago. Steroidogenic and steroid-inactivating enzymes were recruited to regulate steroid-mediated responses as organ function became more complex. For example, in the kidney 11β-HSD-type 2 prevents binding of glucocorticoids to the mineralocorticoid receptor (MR), which is crucial for aldosterone-mediated regulation of electrolyte transport in the distal tubule. We propose that Δ5 steroids, such as dehydroepiandrosterone and its metabolites, were the ligands for the ancestral ER. Understanding the actions of Δ5 steroids in amphioxus and lamprey may shed light on adrenarche and neurosteroid actions in humans.