Steroids

Steroids

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Steroids are a family of lipid molecules that includes cholesterol, steroid hormones, and bile salts. These amphipathic molecules (containing both hydrophobic and hydrophilic regions) are derived from two-carbon acetyl-CoA units, whose combination leads to the formation of isoprenoids (five-carbon isoprene molecular units), and finally to the formation of a seventeen-carbon tetracyclic hydrocarbon, the steroid skeleton. Figure 1 shows the basic steroid skeleton structure, made up of three six-membered rings and one five-membered ring. The fused six-membered cyclohexane rings each have the chair conformation . Each member of the steroid family has a structure that differs from this basic skeleton in the degrees of unsaturation within the ring system and the identities of the hydrocarbon side chain substituents attached to the rings. These substituents are in most cases oxidized to alcohol, aldehyde , ketone , or carboxylic acid functional groups .

The general term sterol refers to a subgroup of steroids that contain an alcohol functional group, which is signified by the -ol ending. Steroids are found predominantly in eukaryotic cells , with cholesterol being the most abundant steroid molecule. It contains twenty-seven carbons, has an alcohol functional group at C-3, a methyl group at C-13, and a branched aliphatic hydrocarbon (eight carbons) unit at the C-17 carbon atom. It is the basic building block for all the other steroid molecules. The biosynthesis of other steroids from cholesterol yields molecules that have fewer carbons, are more polar and more oxidized, and have smaller and more oxidized hydrocarbon units at C-17. It should be emphasized that cholesterol and most steroids contain predominantly single (C–C) bonds and take on non-planar structures. Intracellular cholesterol is predominately found as part of (embedded in) the plasma cell membranes. Because of cholesterol's bulky structure, it does not embed well into the lipid bilayer structure of a membrane and as a result disrupts the order or regularity of the membrane. Increasing levels of embedded cholesterol, which can be as high as 25 percent of membrane volume, correlates with increasing the fluidity (as opposed to rigidity) of the membrane.

The level of extracellular cholesterol in blood serum correlates with the degree of advancement of atherosclerosis and the development of coronary heart disease. The serum cholesterol is obtained from diet and from biosynthesis, which occurs primarily in the liver of mammals. The usual metabolic pathway for cholesterol biosynthesis involves a sequence of more than twenty reactions, each catalyzed by a specific enzyme. The committed and the rate-limiting step in the sequence is the synthesis of a six-carbon molecule, mevalonate, catalyzed by the enzyme 3-hydroxy-3-methylglutaryl CoA reductase (HMG CoA reductase). The development of drugs that inhibit the activity of HMG CoA reductase (and that reduce levels of serum cholesterol), has led to a decline in coronary heart disease. These drugs have structures similar to that of mevalonate and serve as competitive inhibitors of HMG CoA reductase. The binding of a competitive inhibitor to the enzyme and of the substrate mevalonate to the same enzyme are mutually exclusive events. One of the most potent inhibitors of HMG CoA reductase is the drug lovastatin, which binds very strongly at the active site of the enzyme, and, as a result, serum cholesterol levels in humans are decreased by as much as 20 percent.

The hydrophobic, water-insoluble cholesterol is transported in blood to cells predominantly as part of high density and low density lipoprotein particles (HDLs and LDLs, respectively). LDLs transport cholesterol to extrahepatic tissues. The LDL particles bind to LDL receptors on the cell membranes, facilitating cholesterol deposition at the cells, for use primarily as a component of the membrane. HDLs carry out a similar transport function but also return cholesterol to the liver, where it can be metabolized. In this way HDLs decrease the levels of the cholesterol that contributes to the deposition of plaque in arteries and is implicated in heart disease. In a number of cases, patients have been found to have defective genes that code for the LDL receptors. In these cases the LDL particles cannot deposit the cholesterol at cell sites. The LDLs remain in the blood, and eventually their lipid molecules accumulate on the arterial walls, which can lead to blockage of arteries and a heart attack.

Cholesterol is the precursor of other important steroid metabolites , which include bile salts and steroid hormones. Bile salts, which are the major breakdown product of cholesterol, resemble detergents, which are amphipathic molecules (having both polar and nonpolar regions). Their primary function is to emulsify dietary lipids. This interaction between bile salt and lipid increases the surface area of exposed lipid, which greatly enhances the ability of lipase enzymes to get access to and hydrolyze lipid molecules, thereby promoting their absorption and digestion. Bile salts are synthesized and secreted by the liver, stored in the gall bladder, and pass through the bile duct and into the small intestine. Bile salts are the major metabolic product of cholesterol, their manufacture accounting for the consumption of approximately 800 mg/day of cholesterol in a normal human adult. (On the other hand, less than one-tenth that amount of cholesterol is utilized for steroid hormone synthesis.) A major bile salt is glycocholate.

Cholesterol is also the precursor of all the steroid hormones, which can be subdivided into five major classes. The first and second classes of hormones, the mineralocorticoids and the glucocorticoids , are synthesized in the adrenal cortex. The mineralocorticoids (e.g., aldosterone) regulate the body's ion balance by promoting the reabsorption of inorganic ions, such as Na⁺, Cl⁻, and HCO3⁻, in the kidney. As a result, they are involved in the regulation of blood pressure. The glucocorticoids (e.g., cortisol) regulate gluconeogenesis and, in pharmacological doses, inhibit the inflammatory response. The third class includes progesterone , associated with the female reproductive cycle and synthesized in the cells of the corpus luteum; it prepares the lining of the uterus for implantation of the ovum and is essential for the maintenance of pregnancy. The sex hormones are synthesized in the male and female gonads and in the placenta. These hormones, the fourth and fifth classes, are androgens (primarily testosterone) and the estrogens (primarily estradiol). These two classes of hormones are associated with the development of the secondary sexual characteristics of males and females, respectively. They exert powerful physiological effects in humans because of their importance in the regulation of a variety of vital metabolic processes.

Steroid hormones, like all hormones, are chemical messengers. They are synthesized in the cells of an endocrine gland, secreted by the cells into the bloodstream, and travel to target organs in which they direct cell-to-cell communication and the "global regulation" of metabolism in a multicellular organism such as humans. The levels of the steroid hormones are also highly regulated, with levels in the blood or in cells being very small, typically less than micromolar amounts. Because of their hydrophobic

character, they must associate with carrier molecules for their transport in the blood.

In contrast to polypeptide hormones that bind to hormone receptor proteins embedded in the plasma membranes of cells, the hydrophobic steroid hormones pass from the bloodstream into cells readily via passive diffusion across the membrane. Although the steroid hormones can in principle enter all cells, the only cells that are responsive to steroid hormones are those cells that contain proteins called steroid hormone receptors. These receptors reside in an inactive state either in the cytoplasm or in the cell nucleus. There are specific hormone receptors for each of the hormone types: estrogen , androgen, progesterone, glucocorticoid, and mineralcorticoid. As a result of the hormone binding to the recognition site of its hormone receptor, an inactive receptor is transformed into a functionally active one. These active hormone-receptor complexes are ligand -activated transcription factors, which are then able to migrate to the DNA in the nucleus and bind to the promoter regions of a specific subset of genes. This stimulates the transcription of genes that are sensitive to the presence of the hormone. These genes are only expressed or transcribed when the hormone is present. The messenger RNA that is produced is then translated into a new set of proteins. As a result of this stimulation of gene expression, the metabolic character of the cell is dramatically changed.

Anabolic steroids are synthetic substances related to male sex hormones (androgens). Although it is illegal in the United States to possess or distribute anabolic steroids for nonmedical use, a "black market" for them exists, and many amateur and professional athletes take them to enhance performance. In many cases, the athletes take doses that are extremely high—perhaps 100 times the doses that might be prescribed for medical use. As a result, they put themselves in real danger of short-term and long-term health problems. Blood testing, as has been used in the Olympic Games, can detect, identify, and quantify the presence of anabolic steroids in the blood of athletes, which can lead to the disqualification of an athlete.

see also Cholesterol; Cortisone; Estrogen; Lipids; Testosterone.

William M. Scovell

Bibliography

Alberts, Bruce; Johnson, Alexander; Lewis, Julian; Raff, Martin; Roberts, Keith; and Walter, Peter (2002). Molecular Biology of the Cell, 4th edition. New York: Garland Science.

Garrett, Reginald H., and Grisham, Charles M. (1999). Biochemistry, 2nd edition. Fort Worth, TX: Saunders College Publishers.