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MF108 Structural Biochemistry______________________________________________ 1.0 1.

1 INTRODUCTIONS General structural properties of steroids

Steroid is a compound that contains the ring system which contains four rings that are named 1,2-cyclopentano-perhydrophenantrene and each ring is designated to A, B, C and D accordingly. The numbering of the carbons should start with ring A, B, C and D. The carbon are numbered as shown in the diagram below, starting from ring A and subsequently progressing the numbering to ring D, then to the angular (bridgehead) methyl groups usually on position carbon 10 and 13 and finally to side chain linked to the carbon 17.

The naming of the particular steroids can be differ by varying the steroid nucleus with different side chains. Most of the steroids may be named based on the derivatives of this structure, which is called cholestane shown in the above figure. It is to say that all steroids share similar chemistry & nomenclature due to its structural similarities as steroid ring with common numbering system present. Therefore, if there is small changes in structure can dramatically affect the conformation and configuration of the molecule. The presence of different location of different substituents in the ring system will then influence the pharmacological & physiological activity of the steroid. _______________________________________________________________________ _ 1

MF108 Structural Biochemistry______________________________________________ 1.2 Stereochemistry of steroids

The interesting feature of the steroid stereochemistry is that the six-membered rings can present in fixed chair conformations. The two cyclohexane rings can be joined in either a cis or a trans conformation. In cis-decalin, both groups at the ring-junction positions are on the same side of the two rings. However, in trans-decalin, the groups at the ring junctions are on opposite sides. Theoretically the trans isomer is more stable in the structure. The four fused-ring structure can have three dimensional structures in its configurational isomers as the following figure:

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MF108 Structural Biochemistry______________________________________________

2.0 2.1

CLASSIFICATION OF STEROIDS Animal steroids 2.1.1 2.1.2 Insect steroids Metamorphosis hormones: Ecdysteroids such as ecdysterone. Animal steroids Sterol (cholesterol, stigmasterol and vitamin D3) Bile acid and bile salt Steroid hormones Sex hormones i. Female sex hormones - Estrogen - Progestins(progesterone) ii. Male sex hormones (androgen) - Testosterone, - Anabolic steroids Adrenal cortex hormones (corticosteroids) - Glucocorticoids (cortisol or hydrocortisone and cortisone) - Mineralocorticoids (aldosterone)

2.2

Plants steroids

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MF108 Structural Biochemistry______________________________________________ 2.3 Phytosterols Brassinosteroids

Fungus steroids Ergosterols

2.4

Synthetic drugs of steroids Cardiac glycosides (digitalis) Prednisolone

3.0 3.1

STRUCTURAL CHEMISTRY OF DIFFERENT TYPES OF STEROIDS Sterol

Sterol is one of group of steroid alcohol with multi-ring structure and it is the derivatives of steroids with hydroxyl group attached to the carbon 3 of the ring A. This hydrocarbon side chain can poses the polarity in the structure. The alipathic chain including the four ring system shows hydrophobicity or non-polar properties. Thus it is considered as the amphipathic lipids since the structure can have both hydrophilic and hydrophobic characteristics. It can be esterified into the lipid bilayers of the cell membrane. However, sterols only exist in the membranes of eukaryotes, none of the plants have sterols in membranes except mycoplasmas. The following diagram indicates the association of the sterol molecules with the amphipathic cytoplasmic membrane.

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MF108 Structural Biochemistry______________________________________________

We can say that the overall structure results in the water insolubility of the compound as there is only one ionizable residue present in the structure. Sterols and their fatty-acid esters are essentially water insoluble. Sterols sometime contain one or more double bonds in the ring structure and there are also a variety of substituents attached to the rings. In eukaryotic organisms, sterol is most represented by cholesterol and ergosterol (yeast). Besides, stigmasterol is the most common phytosterol in plants. 3.2 Cholesterol

Cholesterol has a molecular formula of C27H45OH and it is composed of a hydrocarbon tail ring structure with 4 hydrocarbon rings as well as a hydroxyl group attached to the carbon 3. The hydroxyl group is polar, which makes it soluble in water and it can exert some alcoholic characteristics. The 4-ring region of cholesterol is the significant of all steroids. Each corner of the ring is composed of a carbon atom, with extending two hydrogen atoms. Cholesterol is regarded as "sterol" in response to the _______________________________________________________________________ _ 5

MF108 Structural Biochemistry______________________________________________ combination of the steroid ring structure and the hydroxyl group. Basically, cholesterol is the animal sterol since there are small amounts of cholesterol made in plants. The hydrocarbon tail is composed of carbon and hydrogen atoms like the steroid. Both the ring region and tail region are non-polar, this is the reason why they are capable of dissolving in fatty and oily substances but is not soluble with water. This make the structure become amphipathic as both a water-soluble region and a fat-soluble region present in the structure. 3.3 Vitamin D

Vitamin D which is called as calciferol and it is a fat-soluble vitamin since it can be synthesized from cholesterol. The figure above shows the structures of vitamin D2 (ergocalciferol) and vitamin D3 (cholecalciferol). 3.4 Bile acid and bile salts

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MF108 Structural Biochemistry______________________________________________

Bile secretion is carried out in the liver and stored in the gall bladder. It is made up of the bile acids or bile salts which contains cholic acid and chenodeoxycholic acid. Both compounds show rigid steroid nucleus and a short aliphatic side chain. This involves 3 six-member rings (A, B and C) and a five member ring (D). The angular methyl groups are present at positions C-18 and C-19. The classification of the structure is based on the side chain of the compound. Cholic acid has an extra hydroxyl residue attached at position C-12 in ring C comparing to chenodeoxycholic acid due to the different synthesis pathway from cholesterol. Bile acids are amphipathic which contain both hydrophobic (lipid soluble) and hydrophilic (polar) properties. 3.5 Female Sex Hormone 3.5.1. Estrogen

Estrogen is derived from terpenes and it carries with 4 condensed rings like others steroid derivatives. A rings has a hydroxyl group and oxygen substituent present while the D ring is extending with an alkyl chain. The classic estrogens are estrone, 17_______________________________________________________________________ _ 7

MF108 Structural Biochemistry______________________________________________ estradiol (most potent), and estriol. Estrogen shows the absence of methyl group in C19 and surprisingly ring A indicates aromatic characteristics.

3.5.2. Progestins

Progesterone is the model molecule of sex hormones. It consists of four interconnected cyclic hydrocarbons. There are ketone and oxygenated functional groups with two methyl branches exit in the structure. It is hydrophobic in nature. 3.6 Male Sex Hormone

3.6.1. Testosterone

Testosterone naturally produced in the human body has the chemical formula C19H28O2. Testosterone is referred as a "bioidentical hormone" which represents the similar chemical structure to natural synthesized hormone. However, chemical modification in _______________________________________________________________________ _ 8

MF108 Structural Biochemistry______________________________________________ the testosterone molecule by adding a side chain or functional group will produce "synthetic" hormone such as methyltestosterone and some anabolic steroids. Androgenic steroid can give effects in the male secondary sexual characterization and male reproductive tract development. 3.7 Adrenal cortex hormones Theoretically, these compounds should be formed in the adrenal cortex. Furthermore, they must be C-21 steroids and three or more oxygen atoms. They have all a en-4-one-3 group and an oxygenated function at C-20. 3.7.1. Glucocorticoids

Cortisol has a general formula of C21H30O5 and it has a hydroxyl group at C-11, C17, and C-21. It is produced by the adrenal cortex which regulates carbohydrate metabolism and controls blood pressure. Cortisol can be used to treat inflammatory conditions and adrenal failure. It may convert to hydrocortisol or cortisone when undergoing the metabolism. 3.7.2. Mineralocorticoids

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MF108 Structural Biochemistry______________________________________________

Aldosterone has one hydroxyl group at C-11 and one aldehyde function at C-18. 4.0 BIOLOGICAL ACTIVITY AND PHYSIOLOGICAL FUNCTIONS OF STEROIDS 4.1 Cholesterol

Sterols are widely distributed and embedded in cell membrane as if in the figure above. Modifications of the steroid ring structure are made by specific enzyme systems, producing the sterol characteristic for each species, such as ergosterol in yeast. The major regulatory step in the sterol biosynthetic pathway occurs early in the process. Drugs that lower blood cholesterol levels in humans are designed to inhibit this regulatory enzyme. In addition to their conversion to sterols, several intermediates in the pathway are precursors of other important biological compounds, including chlorophyll in plants, vitamins A, D, E, and K, and regulators of membrane functions and metabolic pathways. _______________________________________________________________________ _ 10

MF108 Structural Biochemistry______________________________________________ For example cholesterol forms part of the cellular membrane where its presence affects the cell membrane's fluidity and serves as secondary messenger in developmental signaling. Cholesterol also serves as a precursor of steroid hormones (estrogens, androgens, glucocorticoids, and mineralocorticoids) and bile acids. Cholesterol can serve as precursor of all type of steroids. 4.1.1. Maintains the integrity of the cell membranes Cholesterol is an amphipathic molecule which contains a hydrophilic (hydroxyl, OH groups) and a hydrophobic (hydrocarbon tail) portion. The hydrophilic portion of cholesterol aligns with the phosphate heads of the phospholipids while the remaining portion of it tucks into the fatty acid portion of the membrane. Due to the way how cholesterol is shaped, part of the steroid ring, the four hydrocarbon rings in between the hydroxyl group and the hydrocarbon "tail", is closely attracted to part of the fatty acid chain on the nearest phospholipid. This helps immobilize the outer surface of the membrane slightly and make it less soluble to very small water-soluble molecules that could otherwise pass through the membrane more easily. 4.1.2. Helps maintain the fluidity of the cell membranes It helps in preventing the fatty acid chains in the cell membrane from packing together and crystallizing by separating the phospholipids when there is high concentration of cells in the body fluids and thus provides a consistency to the cell membranes. 4.1.3. Helps secure important proteins in the cell membrane The lipid rafts in membranes contain cholesterol with longer and more saturated fatty acid tails. Due to the shape of the cholesterols, they aggregate more in the membrane which leads to the increase of the thickness of the membrane making it ideal _______________________________________________________________________ _ 11

MF108 Structural Biochemistry______________________________________________ for accommodating certain proteins that require special condition to function properly like sticking with other proteins to carry out their functions. 4.1.4. Arteriosclerosis and cholesterol Cholesterol is the most widespread animal steroid and found in almost all animal tissues. For example, egg yolks are rich resource of this compound. Cholesterol is an important component of cell membranes and can serve as intermediate in the biosynthesis of the steroid hormones. However, because it can be synthesized from acetyl coenzyme A, it is usually not a dietary necessity. High levels of cholesterol in blood are associated with atherosclerosis (hardening of the arteries). This condition involves the accumulation of cholesterol and other lipids in the lumen of the arteries.

Figure: Plaque formation on the arteries. Lipoproteins play important roles in the arteriosclerosis disease. It is the carrier for cholesterol and can be classified into HDL(high-density lipoprotein) and LDL(lowdensity lipoprotein). It's often said that HDL is the good cholesterol and LDL is the bad cholesterol. The elevation of the LDL level will deposit the plaque formation on the arteries wall. It results in familial hypercholesterolemia which associates with the LDL defect. The narrowing of arteries will lead to the blockage of the blood flow and cause the _______________________________________________________________________ _ 12

MF108 Structural Biochemistry______________________________________________ blood pressure become higher. This abnormal blood flow will cause the arteriosclerosis to occur. 4.2. Vitamin D

Figure: Biosynthesis activation of cholecalciferol and ergocalciferol by ultraviolet light.

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MF108 Structural Biochemistry______________________________________________ The general structure represents the rings A, B, C, and D with differing side chain residues. Basically, vitamin D3 which is found in human is considered as a seco-steroid which involved the ring opening during the synthesis process. The 7-dehydrocholesterol found in the skin and converted to vitamin D when in contact with ultraviolet light. This process involves the bond breakage that happens in the carbon-9 and 10 in ring B with the presence of ultraviolet light. The conjugated double bond system in the molecule permits the light absorption of UV light at certain wavelengths. This initiates the structure transformations and consequently results in the production of vitamin D3. This can normally occur in the epidermis or skin of most animals. For instance, the exposure of the sunlight is a better way to nourish our body with vitamin D rather than the dietary requirement for this kind of vitamin. Vitamin D can enhance the calcium and phosphorus which can promote their absorption from the skin and deposition in the bone. Poor diet or lack of sunlight can cause rickets and osteomalacia due to the vitamin D deficiency. 4.2.1. Promotes immune function in the skin During wound healing, the expression of the antimicrobial peptide cathelicidin, which can be induced in keratinocytes in vitro by vitamin D3 increases. Besides, the vitamin D3 also induces the expression of Toll-like receptor 2 (TLR2) and the Toll-like receptor cofactor CD14 in wounds and vitro. The increase in TLR2 expression allows keratinocytes to respond to microbial stimulation and also generates an amplification loop, the TLR2 signalling leads to increased expression of 1 -hydroxylase (which is the enzyme that catalysts the conversion of inactive vitamin D3 to active form), and therefore more production of active vitamin D3, which induces the expression of cathelicidin and enhances the expression of TLR2. 4.2.2. Increases the serum calcium concentrations

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MF108 Structural Biochemistry______________________________________________ When the concentration of calcium ions is very low in the body, the parathyroid hormone is induced which in turn stimulates the activation of vitamin D3. The active form vitamin D3 will stimulate the increase of calcium absorption in intestine, increasing osteoclastic resorption, and increasing distal renal tubular reabsorption of calcium. If the calcium ions concentration is too high in the body, the active form vitamin D3 will be suppressed which lead to the decrease in absorption of calcium ions and increase in the excretion of excess calcium ions 4.3. Bile acid and bile salts The metabolism allows cholic and chenodeoxycholic acid to be conjugated with glycine or taurine to give the product of bile salt, which is the conjugated form of bile acids

The metabolism allows cholic and chenodeoxycholic acid to be conjugated with glycine or taurine to give the product of bile salt, which is the conjugated form of bile acids. 4.3.1 Facilitate digestion and absorption of lipid

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MF108 Structural Biochemistry______________________________________________ They are emulsifying agents that have amphipathic molecules with both watersoluble (hydroxyl groups, OH) and water-insoluble or fat-soluble (methyl groups, CH3) parts that make them able to mix fats with water. These groups allow bile acids and salts to break up large globs of fat, connecting to the fat on one side, and connecting to the water on the other, thus mixing the fats and water together by wrapping around the fats. The emulsifying process has increased the surface area of fats and making it available for the digestion enzymes, lipases that are water soluble and cannot access the inside of lipid droplets. 4.3.2 Solubilize and transport lipids in an aqueous environment Their amphipathic nature has enabled them to carry the lipids and solubilize lipids by forming micelles with phosphatidylcholine which are aggregates of lipids such as fatty acids, cholesterol and monoglycerides that remain suspended in water. 4.4. Female Sex Hormone

4.4.1. Estrogen Estrogen refers as the primary female sex hormone. It is present in both men and women, but level of estrogen is higher in female. They stimulate female secondary sex characteristics development, particularly in breasts, thickening of the endometrium and their roles in the menstrual cycle. Follicle stimulating hormone (FSH) and luteinizing hormone (LH) are the key hormone that control the secretion of estrogen. 4.4.1. (i) Stimulate protein synthesis. It stimulates protein synthesis by entering the target cells and binds to a specific receptor molecule to form a complex. The complex is then altered in such a way that it can enter the cell nucleus and bind to nuclear components to promote the transcription of specific messenger RNA (mRNA) which is then translated into specific proteins. _______________________________________________________________________ _ 16

MF108 Structural Biochemistry______________________________________________ 4.4.1. (ii) Promotes secondary growth of female sex characteristics The development of secondary female sex characteristics are stimulated by the estrogens via the promotion of the accumulation of fats at the breast, hips, buttocks and so on. 4.4.1. (iii) Prevent the development of osteoporosis Estrogen blocks the activation of the bone metabolic unit and its effects may be mediated in part by growth factors and interleukins. The estrogen prevents the development of osteoporosis by blocking the synthesis of interleukin 6 which is a potent stimulator of bone resorptions by osteoblast. 4.4.2. Progestins Progesterone has similar pharmacological actions as estrogen. The target sites of this hormone basically will be in the uterus, breast and brain can be done. The development of the secondary endometrium can be done by progesterone. It usually takes part at the end of the menstrual cycle. Progesterone enhances the cervical secretion and reducing cervical penetration by sperm. Progesterone can decrease the contraction of the uterus and thus promote the maintenance of pregnancy. Besides, by the aids of estrogen, it is capable of stimulating the breast lactation during pregnancy. It is to notice that testosterone and estrogen can be made from progesterone as well. 4.4.2. (i) Increase relaxation and reduce anxiety In the brain, the progesterone provide a soothing effect in such a way that is similar to the effects of benzodiazepins by a direct effect on neurotransmitter receptors called Gamma-Amino Butyric Acid type A (GABAA) receptors. The action of progesterone on GABAA receptors has been associated with an increase in appetite and food intake. 4.4.2. (ii) Provide metabolic and nutritional effects _______________________________________________________________________ _ 17

MF108 Structural Biochemistry______________________________________________ It opposes the effect of estrogen in the tendency of storing fat by promoting the use of fat for energy. It also normalizes blood sugar levels by interfering with the action of insulin and counters the binding of estrogen with zinc and copper. 4.4.2. (iii) Involve in treatment of thyroid dysfunction It counteracts the inhibition of thyroid hormone actions by estrogen via keeping zinc and potassium in cells. The keeping of zinc and potassium in cells is important to allow the entrance of thyroid hormone that will be converted into its active form, T3 to carry out its function in the cells. 4.5. Male Sex Hormone

4.5.1. Testosterone Testosterone poses virilizing and anabolic effects Anabolic effects include growth of muscle mass and strength, increased bone density and strength, and stimulation of height growth and bone maturation. Virilizing effect associates with the sex organ maturation especially in penis and scrotum formation in fetuses and at puberty and voice deepening. 4.5.1. (i) Promote erection Testosterone is the precursor of the formation of dihydrotestosterone (DHT) which is the regulator of nitric oxide (NO) and cyclic guanosine monophosphate (cGMP). Both of these compounds involve in the relaxation of smooth muscle that controls the blood vessels within the penis. When the smooth muscles in the tissues of penis relax, the tissues become engorged with bloods and this leads to the erection of penis. 4.5.1. (ii) Protect the brain against Alzheimers disease

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MF108 Structural Biochemistry______________________________________________ The brain is protected against Alzheimers disease through the inhibition of two hallmarks of Alzheimers disease pathology, -amyloid found in senile plaques and hyperphosphorylated tau found in neurofibrillary tangles, by testosterone. The testosterone reduces -amyloid secretion in cortical neurons by altering the processing of the amyloid precursor protein. 4.5.2. Anabolic steroids

The term anabolic is derived from Greek word, it gives the meaning of build up. Some references use the term anabolic-androgenic steroids (AAS) to represent anabolic steroids. Nitrogen-retaining effects of androgen can boost the development of the large muscle mass in males. This is because it has a protein building property which leads to an increase in muscle strength. If comparing the testosterone and anabolic steroid, both of them can play different roles of functional properties in our body. Androgenic activity is essential for male sex drive and performance. It improves secondary sexual characteristics development and play roles in spermatogenesis. Anabolic activity enhances muscle mass development, strength, or endurance. It sometimes functions in the reversion of catabolic process or tissue-depleting conditions.

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MF108 Structural Biochemistry______________________________________________ 4.5.2. (i) Help patients gain weight after a severe illness, injury or continuing infection It helps to increase the bodys ability to use proteins to make muscle by sending the amino acids which are the building blocks of proteins needed by muscle to grow back to the muscles. It also prevents the breakdown of muscle and enhances recovery by inhibiting the binding of cortisol (a stress hormone that is secreted during exercise to enhance the use of proteins for fuel and to suppres inflammation that accompanies tissue injury) to its receptor sites during and after exercise. 4.6. Adrenal cortex hormones

4.6.1. Glucocorticoids Glucocorticoids can be secreted by the outer part of the adrenal gland. It is released during stress conditions and has strong anti-inflammatory actions. 4.6.1. (i) Protects the brains Under stress conditions, cortisol stimulates the breakdown of the structural and functional proteins instead of the brain fats to release amino acids to provide the body energy. These amino acids are then converted into useable carbohydrate (glucose) via the process of gluconeogenesis in the liver. It also inhibits the transport of amino acids into other types of cells and inhibits glucose uptake and oxidation by other cells. 4.6.1. (ii) Helps fight inflammation to minimize cellular damage The cortisol controls the level of inflammation of injuries by influencing the functions of lymphocytes, macrophages and leukoctyes with the utilization of energy to direct their movement to specific locations. Beside that, it also inhibits the production of some cytokines such as interleukin-1 and mediates several components of the _______________________________________________________________________ _ 20

MF108 Structural Biochemistry______________________________________________ inflammatory response. As a result, destruction of the cells caused by inflammatory response can be minimized. 4.6.1. (iii) Decrease inflammation responses Cortisone decreases inflammation (swelling) by preventing infection-fighting white blood cells (leukocytes) from traveling to the area of swelling in the body. For example, in the spine, brain or bone, it can decrease the pressure formed by the inflammation responses on nerve endings and relieve pain. 4.6.2. Mineralocorticoids

Figure: Angiotensin and renin action on blood pressure regulation. Aldosterone has important functions in regulating the electrolyte balance in body. The location of action is mainly kidney and it functions to reduce the rate of sodium-ion excretion with water retention. This will increase the rate of potassium-ion excretion. The secretion of aldosterone appears to be regulated by two mechanisms. When the concentration of dietary sodium ions is limited, rates of aldosterone secretion will be increased. If there is reduced blood flow happens, it stimulates kidney cells to produce _______________________________________________________________________ _ 21

MF108 Structural Biochemistry______________________________________________ the renin, a proteolytic enzyme. It functions in converting the inactive angiotensinogen globulin into angiotensin I(active). After angiotensin I convert into angiotensin II by another enzyme, this promote the aldosterone secretion from the adrenal cortex. It results in retention of salt and water in the blood. By this way, the blood pressure can be easily regulated by the aldosterone with homeostasis effect. However, excessive sodium and water retention will cause edema. 4.6.2. (i) Maintains sodium and water homeostasis Aldosterone helps regulate the bodys electrolyte balance by stimulating reabsorption of sodium and water along with the excretion of potassium. It increases the transport of sodium through the activation and synthesis of epithelial sodium channels in the kidneys, intestine, sweat and salivary glands. The subsequent increased concentrations of sodium in the cells activate Na+/K+ ATPase molecules which transport the sodium back into the bloodstream. 4.6.2 (ii) Regulates acid or base balance When the level of acidity in the body fluid is too high, hydrogen (H+) ions are secreted out from the intercalated cells in the collecting duct which is stimulated by aldosterone together with the reabsorption of sodium and excretion of potassium, into the urine to be excreted out from the body and thus preventing it form binding with bicarbonate (HCO3) to form bicarbonic aicd (H2CO3). When the body fluid is too basic, the bicarbonate ions will be reabsorbed in the kidney to bind with the hydrogen ions to form bicarbonic acid to restore the acid or base balance of the body.

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MF108 Structural Biochemistry______________________________________________ 5.0 5.1 APPLICATIONS AND USES OF STEROIDS Gene therapy Ecdysteroids are use in gene-switch systems as inducers. This means that ecdysteroids are use for gene therapy. These systems are commonly used in vitro with cultured cells, which analyse the role of a wide array of genes. 5.2 Treatment for diseases

5.2.1. Anti-inflammatory properties 5.2.1. (i) Ecdysteroids Ecdysteroids use in wound healing, it had been approved that it can shorten the duration of skin repair. 5.2.1. (ii) Prednisolone It is used to treat arthritis, asthma, bronchitis, colitis, certain skin rashes and allergic or inflammatory conditions of nose and eyes. It can be find in the form of tablets, capsules, liquids, topical creams and gels, inhalers and eye drops, injectable and intravenous solutions. Prednisolone is being used in the treatment of blood cell cancers (leukemias), and lymph gland cancers (lymphomas). It is used as a hormone replacement for whose adrenal glands are not function well. It is usually used for joints pain and itchy skin. Prednisolone is used to reduce the level of calcium in blood and it is used to treat patients who are after having trauma. Prednisone is a synthetic prednisolone.

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MF108 Structural Biochemistry______________________________________________ 5.2.2. Hormonal control 5.2.2. (i) Estrogen Premarin is a synthetic estrogen to overcome menopause symptoms such as hot flashes This estrogen drug is used to promote female gender-specific characteristics in male-to-female transsexuals. Synthetic estrogen is used as birth-control drug, which inhibit the production and secretion of gonadotropin-releasing hormone, luteinizing hormone, and follicle-stimulating hormone.Besides, progestin is synthetic progesterone to reduced menopause symptoms and promote female gender-specific characteristics. 5.2.2. (ii) Testosterone Synthetic testosterone is used to treat infertility, testosterone deficiency in men and symptoms of sexual dysfunction in men and women. It also can use as drugs for femaleto-male transsexuals. It also increase the bone mineral density of testosterone deficiency patient to prevent bone fractures. It also used to prevent dementia and depression. Testosterone is being used to treat women with premature ovarian failure, Turner's syndrome, or HIV infection. 5.2.2. (iii) Others Other steroids like glucocorticoids (Glaucotin) is use specifically to treat Glaucoma. It has been used as clinical or non-prescription drugs for improvement in hyperlipidemia. Sitosterols is one of the phytosterols that used to improve symptom of benign prostatic hyperplasia. Cardiac glycosides (digitalis) is used to treat congested heart failure and supraventricular tachysrhythmias (atrial flutter, atrail fibrillation and paroxysmal supraventricular tachycardia,PSVT).

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MF108 Structural Biochemistry______________________________________________ 5.3 Muscle development for athletes

Figure: The use of anabolic steroids on human. Ecdysteroids was used to stimulate muscle growth, this led to physical performance increased without training. For instance, sportsman can perform better than his usual performances (perform out of his ability) after having this ecdysteroids. It also used as non-toxic muscle-promoting substances for bodybuilders. Some athletes used synthetic testosterone as a physical and performance enhancing drug illegally. It used to increase body mass of organisms. Athletes used anabolic steroids to improve performance. It also used to treat depression and increase a sense of well-being.

5.4

Hormone replacement therapy

Hormone replacement therapy (HRT) involves the participation of synthetic and natural female hormones such as estrogen and progesterone. This is to overcome the lack of natural hormones produced in female. The term estrogen replacement therapy (ERT) is sometimes used. The administration of estrogen and progestin contribute to relieve the menopause, osteoporosis, and reduce the risk of heart disease.

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MF108 Structural Biochemistry______________________________________________ 6.0 6.1 PROS AND CONS OF STEROIDS Advantages of steroids

6.1.1. Role of Steroids to Reduce Inflammation The primary use of steroids in health care is to reduce inflammation and other disease symptoms. This is because steroids make the whole immune system become less active by some mechanism. This is useful and applicable to treat illness where there is an immune component, for example painful joints and ligaments. Steroids cream are used extensively in treating eczema, an inflammatory condition of the skin attended with itching and the exudation of serous matter. The inhaler which is used to treat asthma contains steroid, it has an important in reducing deaths from asthma. Steroids are the ultimate anti-inflammatory drugs. They are prescribed or used only when there is no other way to heal those diseases. The use of steroid in medicine is limited due to very serious side effects in the body. This is the reason why steroids tend to used usually in sprays and creams, which ensure a maximum steroid dose where it is needed, and minimum levels in the blood stream. 6.2 Disadvantages of steroids

6.2.1. Serious Problems due to Steroids Some people need constant prescription of steroid for medical reasons. Knowing that we all need immune systems to fight infections and cancers, but this is always destroyed by steroids. Probably these people are at risk of getting cancer, some of them may be fatal. We see these patterns in those who receive organ transplants, who often need huge doses of steroids to stop the body from destroying the donated tissue. Cancers often develop, which shows us how important our white cells are in keeping us cancer_______________________________________________________________________ _ 26

MF108 Structural Biochemistry______________________________________________ free, and how often all of us develop cancer in our daily lives. Most of us may have two or three tiny cancers inside us at any time. Taking high dose steroids makes it more likely one of these will develop rapidly. People on high dose steroids are immune-deficient in every way so that many organisms that rarely cause problems can overgrow, totally upsetting the normal balance of mircobes in the body. An example is candida yeast which can grow rapidly in the mouth causing painful thrush. 6.2.2. Misuse by Athletes/ Bodybuilders Steroid is sometimes used illicitly by athletes to increase their strength. Those athletes and bodybuilders who wish to get superiority over their counterparts have a tendency of using them. The use of steroids among athletes is legally prohibited. An athlete who takes steroids hormone before the competition can achieve higher levels of performance and get an edge on the competition. In the view of moral, this is unfair for other competitors. However, those who have taken steroid hormone can be clinically tested. The ratio of using steroids is much higher in the bodybuilders as they have no obligation to anyone of its use. In fact, anabolic steroids are not to be used without a doctor's supervision and guidance. It could be fatal and cause certain side effects in the human body, which begin over several days. Many bodybuilders find it difficult to decide whether to use the steroids or not considering its side effects with regard to their health. It is better to take the natural route of bodybuilding rather than taking the route of using steroids. The reason of why the steroid is not a good choice for bodybuilders is that as soon as the bodybuilders leave the intake of steroids, the size of the muscles get reduced. Apart from this, they also lose strength. It looks similar like someone filling air in a balloon and then lets the air out of it. The use of steroids may give to instant results but it will get give side effects over certain of time by endangering the body health. _______________________________________________________________________ _ 27

MF108 Structural Biochemistry______________________________________________ 6.2.3. Health Hazards Typical problems you will find in people who abuse anabolic steroids include liver tumors and cancer, jaundice (yellow skin from liver failure), retention of fluid, high blood pressure, heart attacks and strokes, increases in LDL (dangerous form of cholesterol), kidney cancer, acne and trembling. For men, the side effects include shrinking of the testicles, reduced sperm count, infertility, baldness, development of breasts, increased risk for prostate cancer. For women, steroid stimulate the growth of facial hair, male-pattern baldness, changes in or cessation of the menstrual cycle, enlargement of the clitoris, deepened voice. For adolescents, growth halted prematurely through premature skeletal maturation and accelerated puberty changes. This means that adolescents risk remaining short for the remainder of their lives if they take anabolic steroids before the typical adolescent growth spurt.

6.2.4. Psychological Changes Steroid also affects the brain. Scientific research shows that aggression and other psychiatric side effects may result from abuse of anabolic steroids. Men and women especially with the use of androgenic steroids, high dosages and long-term consumption, can develop aggressive behavior. The advantage of this is that one can train harder and more intensely. The disadvantage is that some cannot properly cope with this, thus letting their aggressions out on others. They become easily irritated, impatient, and inclined toward quick temper and anger outbursts. In extreme cases this can lead to an increase in the use of violence which has caused the breakup of relationships and marriages. _______________________________________________________________________ _ 28

MF108 Structural Biochemistry______________________________________________ Remarkable is that some male athletes using steroids can become depressive. The cause for this may be the fact that these athletes tend to transform a considerable amount of the consumed steroids into estrogens. One can explain the mood swings and depressions with the known fact that the male hypothalamus reacts to the female hormone estradiol. The supposition that steroids would make athletes psychically dependent and, after their discontinuance, evoke withdrawal symptoms, is not totally wrong. Those who press 400 pounds on the bench with the aid of steroids and then, after discontinuing the substance, press only 360 pounds, then 320 pounds, and after a some time only 300 pounds, can suffer problems with their ego. Many athletes simply forget that the performance cannot remain at the same level without steroid use. In the traditional sense, steroids are not habit forming. 7.0 CONCLUSIONS Based on the variety of steroid structures we conclude that steroids can potentially perform essential biological and physiological activity in nature. The subtle differences of its structural activity relationship will determine the general application and uses of steroids. It is believed that steroid in conjunction with its unique 4-membered rings system is capable of contributing to the future research and developments. Modification of the structures by other chemical residues may help to discover more alternative to fulfill our daily needs. However, there are limitations of steroid that may influence the user instead of benefits. Misuses of steroids are prone to sign effect and against the legality. The instructions of steroids usage should be fully obeyed so that to get rid of the unnecessary consequences. We are satisfied with the attendance and contribution of each member of the group except NIL.

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MF108 Structural Biochemistry______________________________________________ 8.0 REFERENCES

1. ALLAIN, P., 2006. Mineralocorticoids: aldosterone[Online]. Pharmacorama Charter. Available from: http://www.pharmacorama.com/en/Sections/CRH_ACTH_corticosteroids_5.ph p. [Accessed 23 February 2008] 2. Anabolic steroids 2006. Vitamin Supplements Guide. Available from: http://www.vitamins-supplements.org/hormones/anabolic-steroids.php [Accessed by: 29-02-2008] 3. BEAUCHET, O., 2006. Testosterone and cognitive function: current clinical evidence of a relationship[Online]. Society of the European Journal of Endocrinology. Available from: http://www.ejeonline.org/cgi/content/full/155/6/773[Accessed 28 February 2008] 4. BELL, E., 2008. Vitamin D3 promotes immune function in the skin[Online]. Nature Publishing Group. Available from: http://www.signalinggateway.org/update/updates/200703/nri2047.html[Accessed 25 February 2008 ] 5. Beta-Ecdysterone and Its findings 2007. Available from: http://www.mdidea.com/products/herbextract/ecdysterone/data.html [Accessed 24 February 2008] 6. BOWEN, R., 2001. Secretion of Bile and the Role of Bile Acids In Digestion[Online]. Available from: http://www.vivo.colostate.edu/hbooks/pathphys/digestion/liver/bile.html [Accessed 26 February 2008] 7. Cassar, M.P., 2004. Cortisol[Online]. Elsevier Health Sciences. Available from:http://books.google.com.my/books?id=ezKPB4S0BdsC&pg=PA70&lpg=PA7 0&dq=functions+of+cortisol&source=web&ots=3Do1XKOEus&sig=6Rj_xqLtdktF ecHwTW_YTdEt1IE&hl=en#PPA70,M1 [Accessed 29 February 2008]

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MF108 Structural Biochemistry______________________________________________ 8. CRAIGHEAD, W.E., and NEMEROFF,C.B., 2002. Physiological Control and Effect of Hormone [Online]. John Wiley And Sons. Available from: http://books.google.com.my/books?id=ayqEGljUVr8C&pg=PA689&lpg=PA689&d q=how+does+estrogen+promote+formation+of+female+secondary+sex+characteris tics&source=web&ots=vbWWGMwSla&sig=4pQxE_NvmQFNnTGryfksnFA79JE &hl=en#PPA689,M1 [Accessed by: 27 February 2008] 9. Dixon, P., 2007. Steroids - The Truth about Steroids[Online]. Available from: http://www.globalchange.com/steroids.htm [Accessed 11 March 2008]. 10. Drugs Used For Treating Patients With Congestive Heart Failure. Available from: http://www2.nau.edu/~daa/lecture/chfmeds.htm.[Accessed 3 March 2008] 11. FABRY, B., et al., 2002. Use of Nanoscale Sterols and Sterol Esters[Online]. Cognis Deutschland GmbH. Available from: http://www.patentstorm.us/patents/6352737-description.html[Accessed 3 March 2008] 12. FORNEY, B., 2006. Prednisone For Veterinary Use[Online]. Wedgewood Village Pharmacy, Inc. Available from: http://www.wedgewoodpharmacy.com/monographs/prednisone.asp. [Accessed 5 March 2008] 13. FRAMBOISE , 2006. Progesterone functions[Online]. Blogger. Available from: http://surmeno.blogspot.com/2006/03/progesterone-functions.html [Accessed 28 February 2008] 14. Generic name: prednisolone 2008. Available from: http://www.medicinenet.com/prednisolone/article.htm[Accessed 3 March 2008] 15. Glaucotin 2007. Available from: http://www.glaucotin.com/about.htm. [Accessed 21 February 2008] 16. Hormone action, cortisol 2008. Institute of Population Health. Available from: http://www.emcom.ca/primer/cortisol.shtml[Accessed by: 29-02-2008] _______________________________________________________________________ _ 31

MF108 Structural Biochemistry______________________________________________ 17. JOHNSON, L.R., and BYRNE, J.H., 2007. Essential Medical Physiology[Online].Academic press. Available from: http://books.google.com.my/books?id=j9etkdHeUoC&pg=PA522&lpg=PA522&dq =functions+of+bile+acids+and+bile+salts&source=web&ots=yZH4_mm2lY&sig= EudzMPBKqGcBq3SIh5e8LaqKkD4&hl=en#PPA522,M1 [Accessed by: 26-022008] 18. KAPITANYAN, R., 2006. Plant Poisoning, Glycosides Cardiac[Online]. HONcode principles of the Health On the Net Foundation. Available from: http://www.emedicine.com/EMERG/topic439.htm [Accessed 3 March 2008] 19. KOMER, 2008. Mens Sexual Functions,Andropause and testosterone[Online]. The Masters Men's Clinic. Available from: http://www.mastersmensclinic.com/male_sexual_function.htm [Accessed 28 February 2008] 20. LAM, M., 2004. Cholesterol [Online]. Available from: http://www.lammd.com/A3R_brief_in_doc_format/Cholesterol.cfm#Cholestero l%20Lowering%20Protocol. [Accessed 5 March 2008] 21. Maglione-Garves, C.A., Kravitz, L., and Schneider, S., 2002. Cortisol Connection: Tips on Managing Stress and Weight[Online]. Available from: http://www.unm.edu/~lkravitz/Article%20folder/stresscortisol.html[Accessed 29 February 2008] 22. MALINA, R.M., BOUCHARD, C., and BAR-OR, O., 2004. Effect of Gonadal and adrenal steroids [Online]. HumanKinetics. Available from: http://books.google.com.my/books?id=VqFcFsykj6EC&pg=PA415&lpg=PA415&d q=how+does+estrogen+promote+formation+of+female+secondary+sex+characteris tics&source=web&ots=ygOQGZsVH7&sig=MvT9bh4UGvv6swbK1yvUh_Sr4vI& hl=en#PPA415,M1 [Accessed 27 February 2008]

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MF108 Structural Biochemistry______________________________________________ 23. MARGO, M., 2006. Testosterone treatment. [Online] American Academy of Family Physician. Available from: http://www.aafp.org/afp/20060501/1591.html. [Accessed 21 February 2008] 24. MASTERJOHN, C., 2005. Cholesterol's Importance to the Cell Membrane[Online] Chris Masterjohn. Available from: http://www.cholesterol-andhealth.com/Disclaimer.html [Accessed by: 24-02-2008] 25. NIESCHLAG, E., 2008. Testosterone [Online], Cambridge University Press . Available from: http://www.cambridge.org/catalogue/catalogue.asp?isbn=9780521833806. [Accessed 21 February 2008] 26. OTT, S., 2002. Estrogen - mechanism of action on bone[Online].Available from: http://courses.washington.edu/bonephys/esteffects.html [Accessed by: 27 February 2008] 27. Prednisone/Prednisolone. Available from: http://www.marvistavet.com/html/body_prednisone.html{Accessed 3 March 2008] 28. Progesterone 2007. Available from: http://www.humanhormones.com/category/steroids/[Accesed 5 March 2008]. 29. Steroid "Headquarters" Learn About Deadly Steroids Now 2005.Show-TechTM. Available from: http://www.muscleenhancers.com/steroids/ [Accessed 11 March 2008] 30. The importance of calcium and vitamin D3, 2007. 5M Enterprises Ltd. Available from: http://www.thepoultrysite.com/publications/1/egg-quality-handbook/6/theimportance-of-calcium-and-vitamin-d3 [Accessed by: 25 February 2008] 31. The Action of Progesterone, 2008. Available from: http://www.yourmenopausetype.com/steroidpathway/actions_of_progesterone.html [Accessed by: 28 February 2008] _______________________________________________________________________ _ 33

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