Harpers

440 / CHAPTER 42HOABCCCDC C CC CCCholesterol side chain cleavageACTH(cAMP)P450sccHO2314191052120CH 3C1812 1711 13 1615149876O+HCC C C COCCholesterolPregnenolone + isocaproaldehydeBasic steroid hormone structuresCH 2 OHOHOHHOCOOHCH 3O CHOOOO17β—EstradiolTestosteroneCortisolProgesteroneEstrane group (C18)Androstane group (C19)Pregnane group (C21)Figure 42–3. Cholesterol side-chain cleavage and basic steroid hormone structures. The basic sterol rings are identifiedby the letters A–D. The carbon atoms are numbered 1–21 starting with the A ring. Note that the estrane grouphas 18 carbons (C18), etc.C 21 hydroxylation is necessary for both mineralocorticoidand glucocorticoid activity, but most steroids with a C 17hydroxyl group have more glucocorticoid and less mineralocorticoidaction. In the zona glomerulosa, which doesnot have the smooth endoplasmic reticulum enzyme17α-hydroxylase, a mitochondrial 18-hydroxylase is present.The 18-hydroxylase (aldosterone synthase) acts oncorticosterone to form 18-hydroxycorticosterone, whichis changed to aldosterone by conversion of the 18-alcoholto an aldehyde. This unique distribution of enzymes andthe special regulation of the zona glomerulosa by K + andangiotensin II have led some investigators to suggest that,in addition to the adrenal being two glands, the adrenalcortex is actually two separate organs.B. GLUCOCORTICOID SYNTHESISCortisol synthesis requires three hydroxylases located inthe fasciculata and reticularis zones of the adrenal cortexthat act sequentially on the C 17 , C 21 , and C 11 positions.The first two reactions are rapid, while C 11 hydroxylationis relatively slow. If the C 11 position is hydroxylatedfirst, the action of 17-hydroxylase is impeded and themineralocorticoid pathway is followed (forming corticosteroneor aldosterone, depending on the cell type).17α-Hydroxylase is a smooth endoplasmic reticulumenzyme that acts upon either progesterone or, morecommonly, pregnenolone. 17α-Hydroxyprogesterone ishydroxylated at C 21 to form 11-deoxycortisol, which isthen hydroxylated at C 11 to form cortisol, the most potentnatural glucocorticoid hormone in humans. 21-Hydroxylaseis a smooth endoplasmic reticulum enzyme,whereas 11β-hydroxylase is a mitochondrial enzyme.Steroidogenesis thus involves the repeated shuttling ofsubstrates into and out of the mitochondria.C. ANDROGEN SYNTHESISThe major androgen or androgen precursor produced bythe adrenal cortex is dehydroepiandrosterone (DHEA).Most 17-hydroxypregnenolone follows the glucocorticoidpathway, but a small fraction is subjected to oxidative fissionand removal of the two-carbon side chain throughthe action of 17,20-lyase. The lyase activity is actuallypart of the same enzyme (P450c17) that catalyzes 17αhydroxylation.This is therefore a dual function protein.The lyase activity is important in both the adrenals and