Corticosterone, synthesis

Metyrapone (Figure 39-5) is a relatively selective inhibitor of steroid 11-hydroxylation, interfering with cortisol and corticosterone synthesis. 

Y1 Mouse adrenocortical tumor Adrenocortical cell Methyl sulfone metabolites of DDT and PCBs Inhibition of corticosterone synthesis by competitive inhibition of cytochrome P450... 

In aged animal models, chronic administration of ginkgo for 3-4 weeks led to modifications in central nervous system receptors and neurotransmitters. Receptor densities increased for muscarinic, 2, and 5-HTla receptors and decreased for B-adrenoceptors. Increased serum levels of acetylcholine and norepinephrine and enhanced synaptosomal reuptake of serotonin have also been reported. Additional mechanisms that may be involved include reversible inhibition of MAO-A and MAO-B, reduced corticosterone synthesis, inhibition of amyloid-beta fibril formation, and enhanced GABA levels. 

Administration of 2,3,7,8-TCDD to rodents was also shown to reduce blood corticosterone levels (Balk and Piper 1984 DiBartolomeis et al. 1987 Mebus and Piper 1986). This effect has been attributed to decreased corticosterone synthesis by decreasing cholesterol side-chain cleavage in the adrenal gland. More recent studies suggested that 2,3,7,8-TCDD may interfere with secretion or synthesis of appropriate, bioactive ACTH from the anterior pituitary gland, which could compromise adrenal steroidogenenesis (Bestervelt et al. 1993). 

The mineralocorticoid aldosterone is also produced by the adrenal cortex and promotes retention of H20 and Na+ and loss of K+ by the kidney. Cortisol is also an agonist of the aldosterone receptor but the level of cortisol is kept low by type 2 11 (Thydroxysteroid dehydrogenase, which converts cortisol to the inactive cortisone (11-dehydrocortisol). Accordingly inhibition of this enzyme by 18(i>-glycyrrhetinic acid (from liquorice) elevates cortisol with consequent effects of H20 and Na+ retention, oedema and hypertension. Further potential sites of interference by plant substances with steroid hormone metabolism include enzymes involved in steroid hormone synthesis such as the cytochrome P450-linked 11 -hydroxylase that catalyses the last step of corticosterone synthesis. 

There have been frequent difficulties relating physiological effects to cyclic AMP levels. For example, adenosine inhibits the effect of noradrenaline on cyclic AMP accumulation in rat fat cells but does not interfere with the lipolytic effect of the catecholamine [58]. Both ACTH and its o-nitrophenyl sulphenyl derivative stimulate corticosterone synthesis in isolated rat adrenal cells to the same maximal rate, but the analogue has a 30- to 100-fold smaller effect than ACTH on cyclic AMP accumulation [60]. 

ACTH derivatives inhibit lipolytic action, cAMP synthesis, corticosterone synthesis, and ACTH activity. 

Copper complex modulation of steroid hydroxylations have also been reported [690]. A single dose of Cu(II)sulphate injected into rats caused a 2-to 3-fold increase in adrenal copper, a significant (P < 0.05) increase in mitochondrial P-450-dependent steroid 11-jS-hydroxylase activity, and an 85% increase in concentration of P-450 as well as a 3-fold increase in fi-aminolevuli-nate synthetase, which suggests a positive feedback stimulation of P-450 synthesis. Chronic treatment with Cu(II)sulphate for 7 days caused a decrease in 11-jS-hydroxylase activity (P<0.05) and a decrease in plasma corticosterone concentration (P<0.05) while there was a concomitant increase in cholesterol side-chain cleavage, suggesting the metabolism of cholesterol by some other P-450 following maximal corticosterone synthesis. A positive feedback for 6-aminolevulinate synthesis was also evidenced by an increase in synthetase activity. 

Haksar a, Maudsley DV, Peron EG and Bedigian E (1976) Lanthanum inhibition of ACTH-stimu-lated cyclic AMP and corticosterone synthesis in isolated rat adrenocortical cells. J Cell Biol 68 142-153. 

A photochemical partial synthesis of aldosterone (19) made the hormone available on an industrial scale for the first time (114). Corticosterone acetate (51 acetate) is treated with nitrosyl chloride in pyridine at 20°C to yield the 11-nitrite (115). Irradiation of (115) leads to rearrangement with formation of the C g-oxime (116). Removal of the oxime residue with nitrous acid furnishes aldosterone (19) in excellent yield. 

The photolysis of nitrite esters has been found to be of considerable synthetic utility, particularly in functionalizing steroid methyl groups. The most spectacular application of this reaction has been a three-step synthesis of aldosterone.<59) Irradiation of corticosterone-11-nitrite (30) followed by nitric acid treatment gave aldosterone (32) in a 15% overall yield ... 

The 17- and 21-hydroxylase enzymes are associated with microsomes, whereas the ll- -hydroxylase has a mitochondrial origin. Since the last-named enzyme is not detectable in other steroid-producing tissues, the term 11-oxygenated steroids is considered synonymous with adrenal steroids. Aldosterone synthesis involves an essential 18-hydroxylation step catalyzed by P450d8 with corticosterone as the precursor this reaction also takes place within the mitochondria. 

Inhibition of adrenocortical synthetic function. Etomidate inhibits the activity of ll-p-hydroxylase, an enzyme necessary for the synthesis of cortisol, aldosterone, 17-hydroxyprogesterone, and corticosterone. Even after a single dose, adrenal suppression persists for 5-8 hours. Although the clinical significance of short-term suppression of cortisol synthesis is unknown, maintenance infusions for anaesthesia cannot be recommended. 

The synthesis of adrenal steroids is illustrated in Fig. 5.3.1. Cortisol, corticosterone, and aldosterone are formed by sequential hydroxylations and oxidoreductions from pregnenolone and progesterone. 17a-Hydroxypregnenolone (17HP) is a branchpoint constituent because it can be converted to cortisol or adrenal androgens. All of the components of this pathway can be quantified by MS/MS. The steroids around the periphery are urinary metabolites and these are measured by GC-MS following hydrolysis of conjugates and derivatization. 

Patients with 11/1-hydroxylase deficiency present with features of androgen excess, including masculinization of female newborns and precocious puberty in male children. There are two human isozymes that are responsible for cortisol and aldosterone synthesis, respectively. The CYP11B1 enzyme (p45011B) converts DOC to corticosterone (B) and 11-deoxycortisol (S or 11-dihydrocortisol) to cortisol (F). It is also capable of 18-hydroxylating DOC but cannot convert to aldosterone. The latter transformation is carried out by CYP11B2 (also known as aldosterone synthase), which encompasses activity for 18-hydroxylation and subsequent 18-oxidation. When CAH is associated with hypertension, deficient lljS-hydroxylase (CYP11B1) is suspected at this time more than ten mutations have been defined in affected individuals [103]. 

In profile analysis, I shows low THAldo and 18-hydroxyTHA (the major 18-hydroxy corticosterone metabolite), but high excretions of THAs and THBs [26, 33]. In II, THAldo is low, the THAs and THBs normal, but 18-OH-THA is often grossly elevated. Representative excretions of several patients with both forms of the disorder are shown in Table 5.3.11. However, it must be emphasized that even if the steroid phenotype appears to have two forms, a single enzyme is responsible for aldosterone synthesis. 

Glucocorticoids Steroids (cortisol, corticosterone) Many diverse effects on protein synthesis and inflammation... 

The step-by-step synthesis of the steroid hormones pregnenolone and progesterone from cholesterol (C27) was presented in chapter 20 (see fig 20.22). Note that pregneno-lone (C2i) and progesterone (table 20.4) (C2 ) are intermediates in the biosynthesis of all of the major adrenal steroids, including cortisol (C2i), corticosterone (C21), and aldosterone (C21). The same two compounds are intermediates in the synthesis of the gonadal steroid hormones, testosterone (C,9) and 17/3-estradiol (CI8). Because the synthesis of all these hormones follows a common pathway, a defect in the activity or amount of an enzyme along that pathway can lead to both a deficiency in the hormones beyond the affected step and an excess of the hormones, or metabolites, prior to that step. 

Similar to the effect on restraint stress, RmHA (10 mg/kg x 2 ip) inhibited the ACTH and P-END response to insulin-induced hypoglycemia, which increases neuronal HA turnover [30-31]. This inhibitory effect was completely or partly reversed by THIOP. Likewise, the responses of the POMC-derived peptides and corticosterone to immune stimulation with the E.coli lipopolysaccharide (LPS) endotoxin, which augmented neuronal HA turnover, were reduced by RmHA pretreatment [39]. The effect of RmHA was equal to that of HA synthesis inhibition by a-FMH [39]. In lactating female rats suckling-induced ACTH secretion was reduced by pretreatment with RmHA (Fig. 6) as well as by a-FMH [32],... 

The adrenocorticotrophic hormone ACTH (corticotropin) stimulates the adrenal cortex to secrete the glucocorticoids hydrocortisone (cortisol) and corticosterone, the mineralocorticoid aldosterone, and a number of weakly androgenic substances, as well as a small amount of testosterone. Aldosterone synthesis is also regulated by renin and angiotensin. 

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