Adrenocortical Hormones Corticosteroids

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A large number of steroid hormones have been isolated and characterized from the adrenal glands. Since they are produced by the adrenal cortex, the outer part of the adrenal glands near the kidneys, they are termed adrenocortical hormones or corticosteroids*. They contain a pregnane C21 skeleton and fall into two main activity groups, the glucocorticoids and the mineralocorticoids, although it is difficult to separate entirely the two types of activity in one molecule. Glucocor-ticoids are concerned with the synthesis of carbohydrate from protein, and deposition of glycogen in the liver. They also play an important role in inflammatory processes. Mineralocorticoids are concerned with the control of electrolyte balance, active compounds promoting the retention of Na+ and Cl-, and the excretion of K+.

Examples of natural glucocorticoids include hydrocortisone (cortisol) and corticosterone (Figure 5.112), whilst aldosterone and desoxy-corticosterone (cortexone) (Figure 5.113) typify mineralocorticoids. Desoxycorticosterone has also been found in plants. Some common features of these molecules are the P-CO.CH2OH side-chain at C-17, and frequently an a-hydroxy also at this position. Ring A usually contains a A4-3-keto functionality. The 11^-hydroxy is essential for glucocorticoid activity. In aldosterone, the principal mineralocorticoid hormone, the methyl

HOa.11

O OH

HOa.11

O OH

hydrocortisone cortisone

(cortisol)

Characteristic features of glucocorticoids:

• C21 pregnane skeleton

• 17P-CO.CH2OH side-chain

corticosterone corticosterone

group (C-18) has been oxidized to an aldehyde, and this is able to react with the 11^-hydroxyl, so that aldosterone exists predominantly in the hemi-acetal form (Figure 5.113). This essentially eliminates the glucocorticoid activity.

The corticosteroids are produced from cholesterol via pregnenolone and progesterone. This involves side-chain cleavage as seen in the biosynthesis of cardioactive glycosides (see page 243) and the same sequence of reactions is operative. From progesterone, the formation of desoxycor-ticosterone, corticosterone, and hydrocortisone (cortisol) (Figure 5.114) requires only a series of hydroxylation steps, catalysed by cytochrome

aldosterone

aldosterone

aldosterone (hemiacetal form)

aldosterone (hemiacetal form)

Characteristic features of mineralocorticoids:

• C21 pregnane skeleton

• 17P-CO.CH2OH side-chain

A4-3-keto (usually)

Figure 5.113

desoxycorticosterone (cortexone)

desoxycorticosterone (cortexone)

cholesterol pregnenolone side-chain degradation via 20,22-dihydroxycholesterol (see Figure 5.92)

NAD+

NAD+

O2 NADPH

17a-hydroxylation cholesterol pregnenolone side-chain degradation via 20,22-dihydroxycholesterol (see Figure 5.92)

O2 NADPH

17a-hydroxylation

O OH

O OH

progesterone 17a-hydroxyprogesterone

21-hydroxylation OH

O2 NADPH

O2 NADPH

desoxycorticosterone

O2 NADPH

aldosterone sequential oxidation of 18-methyl

O2 NADPH

desoxycorticosterone

11ß-hydroxylation OH

O2 NADPH

O OH

11-deoxycortisol

O OH

11-deoxycortisol

O2 NADPH

O2 NADPH

aldosterone

O2 NADPH

sequential oxidation of 18-methyl

O2 NADPH

corticosterone

corticosterone

O2 NADPH

O OH

hydrocortisone (cortisol)

O OH

hydrocortisone (cortisol)

P-450-dependent hydroxylases with NADPH and O2 cofactors. Thus, positions 17, 21 and 11 may be hydroxylated, and the exact order can in fact vary from that shown in Figure 5.114, according to species. It can be seen that production of hydrocortisone from cholesterol actually utilizes cytochrome P-450-dependent enzymes in four of the five steps. The further oxidation of C-18 to an aldehyde via the alcohol allows formation of aldosterone from corticosterone, again involving a P-450 system.

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