The Hydroxylation of Steroids

Three major classes of steroids include sterols, steroid hormones, and bile acids. Perhaps the most important sterol, cholesterol, serves as the precursor of both steroid hormones and bile acids. The synthesis of these compounds requires hydroxylation reactions. In addition, steroid-like substances such as vitamin D also undergo hydroxylation reactions. Many of these reactions are performed by the cytochrome P450 superfamily of enzymes. The many different forms of cytochrome P450 oxidize a wide variety of substrates. Moreover, in recent years, it has become apparent that many of these reactions exhibit remarkable regio- or stereoselectivity. For the most part, hydroxylation serves to increase the polarity of the rather hydrophobic steroids. By increasing their aqueous solubility, the hydroxyl functionalities may make certain substances bioactive. Conversely, oxidation may also facilitate the urinary excretion of the compounds. Many microorganisms are capable of steroid hydroxylation. In addition, competitive, noncompetitive, and mechanism-based inhibitors exist for these reactions. Steroid substances are also used to achieve a number of therapeutic objectives. The pharmacologic potential of these compounds may be altered through hydroxylation.

Steroids such as cholesterol, the steroid hormones, and the bile acids, serve a diverse range of functions (5:59). These compounds are, for the most part, water insoluble. Hence, it is

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n of the 3�-OH group, (3) introduction of OH groups into the 7( and 12( positions, (4) oxidation of C(24) to a carboxylate, and (5) conjugation of this side chain carboxylate with glycine or taurine (15:656)." Once formed, the bile acids are secreted into the gallbladder. The compounds then act as emulsifying agents in the digestion and absorption of fats and fat-soluble vitamins (15:656). One steroid-like substance that undergoes hydroxylation reactions is vitamin D. Initially, cholesterol is converted to 7-dehydrocholesterol (pro-vitamin D3). This compound is then photolyzed by ultraviolet light to pre-vitamin D3. Eventually, pre-vitamin D3 spontaneously isomerizes to give vitamin D3. This compound, however, does not have any biologic activity. Rather, it must first be converted to an active form by hydroxylation reactions in the liver and kidneys. In the liver, hydroxylation of vitamin D3 gives 25-hydroxycholecalciferol. This compound is then transported to the kidneys and further hydroxylated to yield the active hormone, 1(,25-dihydroxycholecalciferol (15:1145-1146). This hormone acts in a synergistic manner with parathyroid hormone to increase serum Ca2+ (15:1145-1146). Steroid hydroxylation reactions are mediated

Category: Medical - T