Corticosteroids biosynthesis

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. 

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

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. 

The secretion of epinephrine by the adrenal medulla is controlled directly by nerve impulses and also by the other stress hormones, namely, corticosteroids. This is illustrated in Figure 16.11. Nerve impulses have a major stimulatory effect on tyrosine and dopamine hydroxylases, whereas glucocorticoids have a major effect on phenylethanolamine methyltransferase. Tyrosine hydroxylase is considered the rate-controlling enzyme in the biosynthesis... 

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-... 

B Mycophenoiate mofetil and other antiproiiferative agents fre-quentiy cause leukopenia and thrombocytopenia. Mycophenoiic acid (active form of mycophenoiate mofetil) inhibits the enzyme inosine monophosphate dehydrogenase, the key enzyme in the de novo pathway for purine biosynthesis. Activated T-lymphocytes cannot use the salvage pathway for purine biosynthesis, and therefore are sensitive to the effects of mycophenoiic acid. The caicineurin inhibitors, IL-2 receptor antagonists, and corticosteroids do not cause bone marrow suppression. 

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.)...

In contrast to the lack of effect on prostaglandin biosynthesis in broken cell preparations , anti-inflammatory steroids exhibit potent inhibitory effects on prostaglandin production in rheumatoid synovial , HSDM-jC mouse fibrosarcoma and MC5-5 mouse fibroblast cultures, as well as in rat synovia and rabbit uvea in vivo 5. Corticosteroids also block the release of prostaglandins in guinea pig lungs perfused with RCS-releasing factor . Available data are consistent with a site of action prior to the release of arachidonic acid . 

Cytochrome P450 isoz3mies Oxidation of steroids Corticosteroid biosynthesis... 

Balm, P.H., J.D. Fambert and S.E. Wendelaar Bonga. Corticosteroid biosynthesis in the interrenal cells of the teleost fish, Oreochromis mossambicus. Gen. Comp. Endocrinol. 76 53-62, 1989. 

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). 

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... 

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