Steroid hormones pathway

Because steroids are lipophilic, they diffuse easily through the cell membranes, and therefore have a very large distribution volume. In their target tissues, steroids are concentrated by an uptake mechanism which relies on their binding to intracellular proteins (or " receptors ", see below). High concentration of steroids are also found in adipose tissue, although this is not a target for hormone action. In the human male, adipose tissue contains aromatase activity, and seems to be the main source of androgen-derived estrogens found in the circulation. But most of the peripheral metabolism occurs in the liver and to some extent in the kidneys, which are the major sites of hormone inactivation and elimination, or catabolism (see below).

Cells of the zona fasciculata and zona reticularis lack aldosterone synthase (CYP11B2) that converts corticosterone to aldosterone, and thus these tissues produce only the weak mineralocorticoid corticosterone. However, both these zones do contain the CYP17A1 missing in zona glomerulosa and thus produce the major glucocorticoid, cortisol. Zona fasciculata and zona reticularis cells also contain CYP17A1, whose 17,20-lyase activity is responsible for producing the androgens, dehydroepiandosterone (DHEA) and androstenedione. Thus, fasciculata and reticularis cells can make corticosteroids and the adrenal androgens, but not aldosterone.

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ONC1-0013B inhibits AR activity in vitro. A. ONC1-0013B structure. B. LnCAP cells cultured (10% CSS) for 3 days, then treated with tested compounds in presence of 1nM DHT for 1 day. PSA expression plotted as percentage of vehicle control (DMSO; n=2, mean±SEM). Ki values: ± (ONC1-13B), ± (MDV3100), (ARN-509). Mean±SEM from 5 replicate experiments (except ARN-509). C. LnCAP cells cultured (10% CSS) for 3 days, then treated with tested compounds in presence of 1nM DHT for 5 days. Viable cells plotted as percentage of vehicle control (DMSO; n=2, mean±SEM). IC50 values: 30nM (ONC1-13B), 148nM (MDV3100), 240nM (ARN-509). D. Competitive-binding assay vs AR ligand Fluormone™ (PolarScreen™ Androgen Receptor Competitor Assay). IC50 values: 19nM (DHT), (ONC1-13B), (MDV3100).

In addition to their characteristic hydroxylase activities, some steroidogenic CYP enzymes also catalyse lyase reactions. Specifically, the CYP11A (cytochrome P450 cholesterol side chain cleavage) and CYP17 (cytochrome P450 17α-hydroxylase/C17,20-lyase) enzymes can each catalyse cleavage of the C․C bond weakened by the hydroxylation reactions. CYP11A acts in the IMM to catalyse the rate-limiting reaction in steroid synthesis: the conversion of cholesterol to pregnenolone. This crucial CYP enzyme hydroxylates two adjacent carbons (C20 and C22) in the D-ring side chain of cholesterol, facilitating cleavage between C20 and C22 to leave the Δ 5 21 carbon steroid, pregnenolone ( Miller 2008 ). Similarly, CYP17 introduces a hydroxyl group at position C17 of either pregnenolone or progesterone, as a result of which the weakened C17–C20 bond breaks to generate either DHEA or androstenedione, respectively ( Miller 2008 ) (see Figure ). Other members of the CYP enzyme family simply catalyse introduction of oxygen to generate hydroxyl groups at specific carbon positions (see Table ). The hydroxylations catalysed by CYP21 (21-hydroxylase) and CYP11B1 (11β-hydroxylase) are pivotal in the formation of corticosteroids by the adrenal cortex ( Miller 2008 ). The hydroxyl group generated at position C18 by CYP11B2 (aldosterone synthase) undergoes rapid oxidation to form an aldehyde group ( Curnow et al 1991 ), hence giving rise to the name ‘aldosterone’ (see Figure ). Finally, CYP19 (aromatase) is the most complex member of the steroidogenic CYP enzyme family, catalysing a series of reactions that convert C19 androgens (androstenedione and testosterone) to their C18 oestrogen metabolites (oestrone and oestradiol, respectively). In this reaction sequence, the C19 methyl group is lost and the ketone at position C3 is reduced to a hydroxyl group ( Miller 2008 ). This liberates electrons which are invested in the A-ring of the steroid to generate the aromatic phenol ring, the hallmark of oestrogens (see Figure ) and a prerequisite for activation of the oestrogen receptor.

Steroid hormones pathway

steroid hormones pathway

ONC1-0013B inhibits AR activity in vitro. A. ONC1-0013B structure. B. LnCAP cells cultured (10% CSS) for 3 days, then treated with tested compounds in presence of 1nM DHT for 1 day. PSA expression plotted as percentage of vehicle control (DMSO; n=2, mean±SEM). Ki values: ± (ONC1-13B), ± (MDV3100), (ARN-509). Mean±SEM from 5 replicate experiments (except ARN-509). C. LnCAP cells cultured (10% CSS) for 3 days, then treated with tested compounds in presence of 1nM DHT for 5 days. Viable cells plotted as percentage of vehicle control (DMSO; n=2, mean±SEM). IC50 values: 30nM (ONC1-13B), 148nM (MDV3100), 240nM (ARN-509). D. Competitive-binding assay vs AR ligand Fluormone™ (PolarScreen™ Androgen Receptor Competitor Assay). IC50 values: 19nM (DHT), (ONC1-13B), (MDV3100).

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