Ho

corticosterone P450c11AS

P450c11ß

cortisol

corticosterone P450c11AS

cortisol

CH2OH C=O

aldosterone Zona Glomerulosa aldosterone Zona Glomerulosa

Zonae Fasciculata and Reticularis

FIGURE 4 Biosynthesis of adrenal cortical hormones. The pathway on the left represents that found in the zona glomerulosa. The pathways on the right are followed in the zonae fasciculata and reticularis. Hydroxylation at carbon 17 usually precedes hydroxylation at carbon 11. Note that changes produced in each reaction are shown in blue.

adrenal steroids and appears necessary for physiologic activity. Biosynthesis of the various steroid hormones involves oxygenation of carbons 21, 17, 11, and 18, as depicted in Fig. 4. The exact sequence of hydroxylations may vary, and some of the reactions may take place in a different order than that presented in the figure. The specific hormone that is ultimately secreted once the cholesterol-pregnenolone road block has been passed is determined by the enzymatic makeup of the particular cells involved. For example, two different P450 enzymes catalyze the hydroxylation of carbon 11. One of these is found exclusively in cells of the zona glomerulosa (P450c11AS) and catalyzes the oxidation of both carbon 11 and carbon 18. The other enzyme (P450c11j) is found in cells of the zonae fasciculata and reticularis and can oxidize only carbon 11. At the same time, cells of the zonae fasciculata and reticularis, but not of the zona glomerulosa, express the enzyme P450c17, also called

P450 17a-hydroxylase/lyase, which catalyzes the oxidation of the carbon at position 17. Hence, glomerulosa cells can produce corticosterone, aldosterone, and deoxy-corticosterone, but not cortisol, while cells of the zonae fasciculata and reticularis can form cortisol and 17a-hydroxyprogesterone. When reducing equivalents are delivered to P450c17 rapidly enough, the reaction continues beyond 17a-progesterone hydroxylation to cleavage of the carbon 17-carbon 20 bond. Removal of carbons 20 and 21 produces the 19-carbon androgens. Hence androgens can also be produced by these cells but not by glomerulosa cells.

As is probably already apparent, steroid chemistry is complex and can be bewildering; but because these compounds are so important physiologically and ther-apeutically, some familiarity with their structures is required. We can simplify the task somewhat by noting that steroid hormones can be placed into three major categories: those that contain 21 carbon atoms, those that contain 19 carbon atoms, and those that contain 18 carbon atoms. In addition, there are relatively few sites where modification of the steroid nucleus determines its physiologic activity.

The physiologically important steroid hormones of the 21-carbon series are as follows:

1. Progesterone, which has the simplest structure, can serve as a precursor molecule for all of the other steroid hormones. Note that the only modifications to the basic carbon skeleton of the 21-carbon steroid nucleus are keto groups at positions 3 and 20. Normal adrenal cortical cells convert progesterone to other products so rapidly that none escapes into adrenal venous blood. Progesterone is a major secretory product of the ovaries and the placenta.

2. Addition of a hydroxyl group to carbon 21 of progesterone is the minimal change required for adrenal corticoid activity. This addition produces 11-deoxy-corticosterone, a potent mineralocorticoid that is virtually devoid of glucocorticoid activity. Deoxy-corticosterone is only a minor secretory product of the normal adrenal gland but may become important in some disease states.

3. A hydroxyl group at carbon 11 is found in all gluco-corticoids. Adding the hydroxyl group at carbon 11 confers glucocorticoid activity to deoxycorticosterone and reduces its mineralocorticoid activity 10-fold. This compound is corticosterone and can be produced in cells of all three zones of the adrenal cortex. Corticosterone is the major glucocorticoid in the rat but is of only secondary importance in humans.

4. Corticosterone is a precursor of aldosterone, which is produced in cells of the zona glomerulosa by oxidation of carbon 18 to an aldehyde. The oxygen at

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