Steroids

Chemistry: Foundations and Applications, (2004) by William M. Scovell

Steroids

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.

Figure 1. Steroid skeleton.

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.