Biosynthesis of corticosteroids

Pellagra (characterized by diarrhoea, dermatitis and dementia). Clinical deficiency is not known (has role in biosynthesis of corticosteroids). 

Other risk groups are various stress groups since ascorbate fulfills a function in the biosynthesis of corticosteroids and other hormones. Such studies are planned but because of the nature of the experimental setup, they are not easily carried out. Other groups of potential interest are alcoholics, obese people, and certain diseased or injured patients where the metabolic handling of ascorbate may be widely different from that of normal humans. 

Figure 51-6 Biosynthesis of corticosteroids. Roman numerals I (side-chain cleavage enzyme), II (3-p-ol dehydrogenase and/or A" isomerase), III (21-hydroxylase), and IV (lip-hydroxyiase) indicate sites of major blocks that cause adrenogenital syndromes. (Copyright 1959 CIBA Pharmaceutical Co. Division of CIBA-GEIGY Corp. Reproduced, with permission, from The CiBA Collection of Medical Illustrations by Netter FH.AII rights reserved.)...

Hydroxylation of Adrenal Steroids Studies of the biosynthesis of corticosteroids by adrenal glands, either perfused, minced, or in isolated mitochondria do not reveal any increased reaction with ascorbic acid, although the high ascorbic acid content of the adrenals has prompted many such experiments. Under certain conditions such an effect can be observed on the hydroxylation reactions which require molecular oxygen. An example of such a reaction is the... 

Some of these reactions have great physiological significance, because they represent key transformations in metabolism, as in lipid metabolism and biosynthesis of corticosteroids, for example.Cytochrome P-450 is also known to catalyze the transformation of certain precarcinogens such as benzpyrene into their carcinogenic forms. 

The four corticosteroids, corticosterone, cortisol, cortisone and aldosterone, are structurally and biosynthetically related (see Fig. 10.1, p. 161). The principal ones are corticosterone and aldosterone. The former is present in the highest concentrations in plasma. The ratio corticosteronealdosterone in plasma is approximately 14 1 in domestic fowl, and 63 1 in the duck (Harvey, Scanes Brown, 1986). The enzymes together with P-450 cytochrome, which catalyse the biosynthesis of corticosteroids, are present on the endoplasmic reticulum. 

A steroid female sex-hormone secreted by the corpus luteum during the second half of the menstrual cycle when it prepares the uterus for the implantation of the embryo. It is also secreted by the placenta during pregnancy. The adrenals and testes also secrete small amounts of progesterone since it is an intermediate in the biosynthesis of corticosteroids and androgens. The major urinary metabolite of progesterone is pregnanediol. 

The existence of mitochondrial cytochrome P450 in adrenal cortex was reported originally by Harding et al (1964) and confirmed by subsequent studies. Adrenal cortical mitochondria catalyze a number of NADPH- and molecular-oxygen-dependent hydroxylation reactions that contribute to the biosynthesis of corticosteroids. The enzyme system for 11 jS-hydroxyla-tion has been isolated, and a successful reconstitution of its activity has been achieved by the interaction of three proteins, namely an NADPH-dependent flavoprotein (adrenodoxin reductase), an iron-sulfur protein (adrenodoxin), and the heme protein (cytochrome P450) that serves as the terminal oxidase for the electron transport system from NADPH to oxygen (Wang and... 

Agents targeting the excessive immune response or cytokines involved in IBD are potential treatment options (Table 16-3). Azathioprine and its active metabolite 6-mercaptopurine (6-MP) are inhibitors of purine biosynthesis and reduce IBD-associated GI inflammation. They are most useful for maintaining remission of IBD or reducing the need for long-term use of corticosteroids. Use in active disease is limited by their slow onset of action, which may be as long as 3 to 12 months. Adverse effects associated with azathioprine and 6-MP include hypersensitivity reactions resulting in pancreatitis, fever, rash, hepatitis, and leukopenia.25,26... 

H15. Hammond, G. L., Smith, C. L., and Underhill, D. A., Molecular studies of corticosteroid binding globulin structure, biosynthesis, and function. J. Steroid Biochem. Mol. Biol. 40, 755-767 (1991). 

One class of agents which inhibits LT production in stimulated cell systems, but probably not by direct 5-LO inhibition, is the anti-inflammatory corticosteroids, represented by dexamethasone (10) [30-34]. The well-known inhibition of PG production seen with eorticosteroids is not due to direct CO inhibition, but has been attributed to the inhibition of arachidon-ic acid mobilization by phospholipase A2, caused by enhanced biosynthesis of one or more proteins called lipocortins [35] (although this hypothesis is now being seriously questioned [36]). More recent evidence indicates the possibility of down-regulation of CO enzyme levels [37-39] similar mechanisms involving altered gene regulation could be involved in the observed effects on LT production as well. 

Biosynthesis in anterior pituitary, stimulation of formation of corticosteroids in adrenal cortex, release of fatty acids from adipose tissue,... 

Sterols and Cholesterol. Natural sterols are crystalline C76 C1(1 steroid alcohols containing an aliphatic side chain at C17. Sterols were first isolated as lionsaponifiable fractions of lipids from various plant and animal sources and have been identified in almost all types of living organisms. By far, the most common sterol in vertebrates is cholesterol (8). Cholesterol serves two principal functions in mammals. First, cholesterol plays a role in the structure and function of biological membranes.. Secondly, cholesterol serves as a central intermediate in the biosynthesis of many biologically active steroids, including bile acids, corticosteroids, and sex hormones. 

Aminoglutethimide is a nonsteroidal inhibitor of corticosteroid biosynthesis. It results in decreased production of endogenous estrogens, androgens, and cortisol. It has been used to treat patients with breast cancer, and off-label uses include treatment of prostate cancer. Because this is a rela-... 

Progesterone is the natural hormone that is essential for the initiation and maintenance of pregnancy. Progesterone is also a central intermediate in the biosynthesis of androgens, estrogens and corticosteroids (Scheme 6.1). 

V8. Visser, H. K. A, and Cost, W. S., C21-Corticosteroid excretion pattern in a familiar salt-losing syndrome. A new enzyme defect in the biosynthesis of aldosterone. Acta Endocrinol. Suppl. 89, 31-32 (1964). 

Alclometasone is a topical glucocorticoid with antiinflammatory, antipruritic, and vasoconstrictive properties. It acts by inducing phospholipase A2 inhibitory proteins, thus controlling biosynthesis of potent mediators of inflammation. Alclometasone (0.05% ointment) is a topical adrenocorticoid with antiinflammatory properties that is indicated in inflammation of corticosteroid-responsive dermatoses. 

Agents that inhibit steps in the steroidogenic pathway and thus alter the biosynthesis of adrenocortical steroids are discussed, as are synthetic steroids that inhibit glucocorticoid action. The effects of corticosteroids are numerous and widespread, and include alterations in carbohydrate, protein, and lipid metabolism maintenance of fluid and electrolyte balance and preservation of normal function of the cardiovascular system, the immune system, the kidney, skeletal muscle, the endocrine system, and the nervous system. 

The drug is a purely synthetic compound which possesses a distinct unique characteristic feature of inhibiting 11 -P-hydroxylation in the biosynthesis of cortisol, corticosterone and aldosterone. Therefore, it is invariably employed to test for hypothalamic-pituitary function. However, in the normal individual, the drug essentially blocks the specific enzymatic step that ultimately leads to the synthesis of cortisol and corticosterone in vivo), causing an absolute intense stimulation of adrenocorticotropic hormone (ACTH) secretion and inducing thereby a marked and pronounced enhancement in the urinary excretion of 17-hydroxy-corticosteroids. 

Danon, A. and Assouline, G. (1978). Inhibition of prostaglandin biosynthesis by corticosteroid requires RNA and protein synthesis. Nature (London), 273, 552-554... 

Biosynthesis of prostaglandins is also inhibited by corticosteroids such as hydrocortisone, but by a different mechanism. They act on DNA to induce synthesis of a polypeptide known as macrocortin, about 15000 daltons in size, and this inhibits the phospholipase that releases arachidonic acid from membranes, as described above (Blackwell a/., 1980). 

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