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HYDROXYLATION OF STEROIDS.
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Examines reaction required for synthesis & alteration of pharmacological potential & metabolic functioning.... More...
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Paper Abstract:
Examines reaction required for synthesis & alteration of pharmacological potential & metabolic functioning.
Paper Introduction:
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
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For instance, glucocorticoid is typicallyadministered to reverse the symptoms of 21-hydroxylase deficiency (14:474-482). Literature Cited 1. Eventually, pre-vitamin D3 spontaneously isomerizes togive vitamin D3. San Francisco, CA: W. Groh, H.; Schade, K.; Horhold-Schubert, C. This binding increases the hormone'saffinity for DNA (14:854-855). Johnston, J. Cytochromeswere initially found to be involved in respiration. Rather, it must first be converted to an active form byhydroxylation reactions in the liver and kidneys. Steroids such as cholesterol, the steroid hormones, and the bileacids, serve a diverse range of functions (5:59). Defects in steroidogenic enzymes. In contrast,the steroid hormones are comprised of less than 21 carbon atoms. Various inherited disorders of steroid hormone synthesis result fromhydroxylase deficiencies. J.; Gonzalez, F. In males, while the sexual organs appearnormal at birth, sexual precocity generally becomes apparent within severalmonths (14:474-482). M.; Estabrook, R. Discrepancies between clinical steroid research and molecular biology results. 47:1981-1988; 199 . 7. Subsequent research has observed that cytochrome enzymes "dominatehepatic metabolism (11:17-34)." This is because their "broad andoverlapping sensitivities for xenobiotic lipophilic substrates" enable theenzymes to oxidize a wide variety of substrates. In addition, mechanism-basedor "suicide" inactivation of cytochrome P45 can be accomplished by theacetylenic steroids (6:2159-2162). Initially, 17-hydroxypregnenolone andprogesterone become 17-hydroxyprogesterone. Chen, Z.; White, C. Yet another inherited enzyme deficiency, 11-hydroxylase deficiency,interferes with the conversion of 11-deoxycortisol to cortisol anddeoxycorticosterone to corticosterone. These include the followingcategories: (1) the progestagens; (2) the glucocorticoids; (3) themineralocorticoids; (4) the androgens; and (5) the estrogens. C.; Eaton, D. Moreover, such substances as primaquine and tolbutamide actas noncompetitive inhibitors of the reaction. Perhaps the most important sterol, cholesterol, serves asthe precursor of both steroid hormones and bile acids. G. The regulation of these activities appears to be determinedby the availability of P45 reductase. Furthermore,the reactions exhibit "remarkable regio- or stereoselectivity" for certainsubstrates (9:4419)." In fact, this characteristic can be used as a"sensitive fingerprint for the identification of a specific type ofcytochrome P45 (2:454-462)." In particular, many members of the P45 IIfamily are exceptionally stereospecific and regioselective. Then, the bond between C-2 and C-22 iscleaved by desmolase. R. Indeed,through their effects on gene expression, the steroid hormones "induce thesynthesis of numerous metabolic enzymes in their respective target tissues(15:1146-1148)." As an example, estradiol binds to a specific receptor in thecytoplasm of the uterine cell. American Journal of Obstetrics and Gynecology. 6. All of the reactions require NADPH and O2.The incorporated hydroxyl group's oxygen atom typically comes from the O2rather than from H2O: One molecule of the O2 molecule's oxygen atoms goesinto the substrate, and the other is reduced to water. NADPH transfers its high-potential electrons to an electron-transport chain flavoprotein. The subsequent oxidation of the C-18 angularmethyl group to an aldehyde ultimately gives aldosterone. (1987) found that several drugs andsteroids act as competitive inhibitors of ethinyl estradiol 2-hydroxylation. In females, this cancause virilization: the external genitalia are masculinized duringdevelopment of the female fetus. For example, the main estrogenic component of oralcontraceptives is 17(-ethinylestradiol. Chemical structure of corticosteroids and its relationship with their acute induction of lordosis in the female rat. 5. In addition to estrogen, other steroid hormones are also used forvarious medical purposes. These compounds are, forthe most part, water insoluble. By making hydrophobiccompounds more water-soluble, hydroxylation reactions facilitate theirurinary excretion. Measurement of steroid hydroxylation reactions by high-performance liquid chromatography as indicator of P45 identity and function. The formation of an aromaticring requires the enzyme aromatase. With diminished production of glucocorticoids andmineralocorticoids, there is an overproduction of adrenocorticotropichormone. Typically, the reactions are performed by cytochrome P45 enzymes. Such compounds are potentially capable of interacting with thecardiac glycoside receptors of heart muscle (1 :337-352). 53:159-164; 1995, June.----------------------- 15 33:59-72; 1993. Conversely, oxidation may also facilitate the urinary excretionof the compounds. Inhibition of oral contraceptive steroid- metabolizing enzymes by steroids and drugs. Steroid hydroxylation can additionally be inhibited by variouscompounds. From progesterone, continued chemical transformations can produce theglucocorticoids, the mineralocorticoids, the androgens, or the estrogens.Highly specific hydroxylations at C-17, C-21, and C-11 produce theglucocorticoid, cortisol. Arlotto, M. For example, apatent has already been taken for the fungal preparation ofanticholesterolemic compounds. Microbial transformation of steroids: Contribution to 14(-hydroxylations. A strain of Mycobacterium is used toperform a 9(-hydroxylation resulting in the formation of 9(-hydroxy-3-oxo-stigmast-4,24(25)-dien-26-oic acid. A.; Burnett, V. L. This compound undergoes 2-hydroxylation, methylation, and glucuronidation prior to being excreted.In humans, the major catalyst for the hydroxylation reaction is livermicrosomal cytochrome P45 IIIA4 (also known as P45 NF). Obviously, hydroxylation reactions are very important in steroidchemistry. Zachmann, M. Once thehormones have entered their target cells, they bind to cytoplasmicreceptors, enter the nucleus, and act as transcription factors. The Hydroxylation of Steroids Three major classes of steroids include sterols, steroid hormones,and bile acids. The synthesis ofthese compounds requires hydroxylation reactions. The first step in the synthesis of steroid hormones is stimulated byadrenocorticotropic hormone secretion in the anterior pituitary. Cleavage of the C-2 side chain thengives the androgen, androstenedione. Theconcentration of bacteria generally increases from the jejunum through theileum to the colon. One steroid-like substance that undergoes hydroxylation reactions isvitamin D. At least 2 , and "perhaps as may as 3 -5 " individualforms of cytochrome P45 occur in liver (1:21327). Hydroxylation reactions are also involved in the conversion ofcholesterol to bile acids. Cytochrome P-45 C21scc: One enzyme with two actions: Hydroxylase and lyase. Withfurther scientific advances, the cytochrome P45 enzymes of variousmicroorganisms may one day be employed to enhance the pharmacologicpotential of different steroid compounds. Important genera include Bacteroides, Eubacterium,Bifidobacterium, Fusobacterium, Lactobacillus, Peptostreptococcus,Proprionibacterium, and others (5:59-72). 9. Guengerich, F. It gives rise to fivedifferent types of steroid hormones. Initially, cholesterol is converted to 7-dehydrocholesterol(pro-vitamin D3). Substances which are reabsorbed are typicallytransported to the liver where they undergo further metabolization. The synthesis of the mineralocorticoid, aldosterone, requires thehydroxylation of progesterone at C-21. In contrast,another estrogen, estrone, is derived--through aromatic ring formation--directly from androstenedione (14:474-482). Structural determinants of cytochrome P45 2B1 specificity: Evidence for five substrate recognition sites. This compoundis then transported to the kidneys and further hydroxylated to yield theactive hormone, 1(,25-dihydroxycholecalciferol (15:1145-1146). W. Biochemistry. P.; Trant, J. 8. The hydroxylation of steroids additionally has various pharmacologicimplications. Thechemical structure of cholesterol contains 27 carbon atoms. F. Decreased expression of cytochrome P45 mRNAs and related steroid hydroxylation activities in hepatic hyperplastic nodules in male F344 rats. The compounds then act as emulsifyingagents in the digestion and absorption of fats and fat-soluble vitamins(15:656). In addition, competitive, noncompetitive, and mechanism-based inhibitors exist for these reactions. American Journal of Obstetrics and Gynecology. J. Intestinal tract bacteria can also hydroxylate steroids. Toxicology and Applied Pharmacology. Microbial transformations of steroids. The chemical mechanism which results in aromatic ring formation, however,remains incompletely understood. Hall, P. In the liver,hydroxylation of vitamin D3 gives 25-hydroxycholecalciferol. Similarly, the conversion of progesterone to androstenedione requiresa C17,2 -lyase. From testosterone, loss of the C-19 angularmethyl group and aromatic ring formation yield estradiol. O.; Wright, C. 6 :337-352; 1995, April.11. Thiscompound--which is derived from acetyl coenzyme A--represents an integralcomponent of eukaryotic membranes (14:474-482). This intermediate is then able tocovalently bind to the enzyme molecule (11:17-34). For instance, Purba et al. P. The steroid hormones provide complex chemicalsignalling systems for the coordination of various physiologic events. P.; Gillette, J.; Gelboin, H. W. In addition, the enzyme is also responsible for whether ornot the pathway proceeds to a C-21 steroid such as cortisol or to a C-19sex steroid. With further reduction of the 17-ketogroup, testosterone is formed. H. 2 6:454-462; 1991. He, Y.; Luo, Z.; Klekota, P. Journal of Basic Microbiology. The many different forms of cytochrome P45 oxidize a widevariety of substrates. Voet, D.; Voet, J. Last, androgens and estrogens are formed by the gonads(15:1146-1148). High levels of this substance generally lead to enlargement ofthe adrenal glands and elevated levels of androgens. Moreover, the enzymecan be induced by barbiturates and rifampicin. For example, the fungi Mucorgriseocyanus, Actinomucor elegans, and Thamnostylum piriforme have all beenshown to introduce a hydroxyl group at the 14(-position of progesterone andsome other steroids. Levels ofcytochrome P45 IIIA4 vary widely among individuals. Ball, P.; Knuppen, R. Inaddition, they stimulate the degradation of fat and protein, and alsoinfluence different vital functions involving the body's ability to copewith stress (15:1146-1148). Then, it has been hypothesized thatwhen the monooxygenase delivers an activated oxygen to the acetylenic bond,it forms a transient reactive oxirene. This activation is typically achieved by a superfamily of enzymeswhich have an absorption maximum at 45 nanometers when complexed withcarbon monoxide (14:474-482). Steroid substances are alsoused to achieve a number of therapeutic objectives. Moreover, in recent years, it has become apparentthat many of these reactions exhibit remarkable regio- orstereoselectivity. This typically results in an increase inblood volume and blood pressure (14:474-482). Despite thisstructural similarity, however, the various steroid hormones havedistinctly different functions. Journal of Steroid Biochemistry and Molecular Biology. Asthey are generally hydrophobic, the hormones are transported in the bloodin combination with the glycoprotein, transcortin and albumin. More recently, however, steroid-transforming fungi have been used to achieve chirality. Hu, S.; Genain, G.; Azerad, R. This process involves the following steps:"(1) saturation of the 5,6-double bond, (2) epimerization of the 3ß-OHgroup, (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 chaincarboxylate with glycine or taurine (15:656)." Once formed, the bile acidsare secreted into the gallbladder. The sterol, cholesterol, serves as the major steroid precursor. They are involved in the different compounds' biosynthesis andthe excretion. Metabolism of 17(-ethynylestradiol in humans. This compound subsequentlybecomes 11-deoxycortisol, and then cortisol (15:656-657). Steroid hydroxylation reactions are mediated by monooxygenases (ormixed-function oxygenases). Hence, it is primarily through differenthydroxylation reactions that the compounds achieve their variousphysiologic effects. 3. As with 21-hydroxylase deficiency,11-hydroxylase deficiency also causes adrenal enlargement (16:159-164).Similarly, 11-hydroxylase deficiency can also cause high levels ofandrogens and virilization (14:474-482). Steroid metabolism with intestinal microorganisms. 264:21327- 21333; 1989, December 15. These enzymes arecapable of hydroxylating hundreds of structurally diverse, low molecularweight lipophilic compounds including such foreign compounds as drugs,carcinogens, and plant products. The hormone's primary function is to prepare thelining of the uterus for implantation of an ovum. 17-Hydroxyprogesterone can also be further oxidized to producedehydroisoandrosterone (15:656-657). Second edition. This 14(-hydroxy compound can then be transformed bya 14ß,15ß-epoxide to a 14ß-hydroxy substituent found in cardioactivesteroids. Methods in Enzymology. In addition to promoting urinary excretion, cytochrome P45 enzymeshydroxylations are also involved in biosynthesis (11:17-34). The three reactions ultimately form the "keyintermediate in the synthesis of steroid hormones," pregnenolone (14:474-482). Smith, K. Biochemistry. V.; Waxman, D. The mineralocorticoids increase reabsorption of Na+,Cl-, and HCO3- by the kidney. 2. Life Sciences. The Journal of Biological Chemistry. Second, the compound's >5 double bond is isomerized to a >4double bond (14:474-482). The complex enters the nucleus, binds tothe DNA in a highly specific manner, and eventually stimulates uterinegrowth (4:151-152). 163 (6 Part 2):2163-217 ; 199 , December. 4 :527-532; 1991. Formation, metabolism, and physiologic importance of catecholestrogens. Thus, this potentialvariability in the rate of 17(-ethinylestradiol hydroxylation can affectthe contraceptive's pharmacokinetics: Increases in the compound's rate ofclearance could diminish its effectiveness (7:1981-1988). Sequence requirements for cytochrome P-45 IIB1 catalytic activity. The electrons are then transferred to anonheme iron protein, adrenodoxin. The most common of these is 21-hydroxylasedeficiency. P. In addition to pharmacologic products,microorganisms may also be employed in the agrochemical industry for theproduction of herbicides and pesticides; fungi could even be used in thefood industry to create flavors and essences (13:1 77-1 8 ). The hydroxylation of steroids generally requires the activation ofoxygen. During passage through theintestinal system, sterols and steroids may be transformed, reabsorbed, orexcreted in feces. Hence,the synthesis of steroids initially requires the removal of a C6 sidechain. It is this compound which transfers oneelectron to the oxidized form of cytochrome P45 . 24:443-449; 199 , December.13. New York, NY: John Wiley & Sons; 199 .16. Biochemistry. E.; Ahmed, F.; Antoniou, T. In addition, steroid-like substances such as vitamin D also undergo hydroxylation reactions.Many of these reactions are performed by the cytochrome P45 superfamily ofenzymes. These reactions produce 1,2- and 4,5-arenoxides in equilibrium with keto- and oxepin tautomers as intermediates. In fact, the acetylenic analogs ofandrostenedione (Plomestane) and deoxycorticosterone (18-acetylenicdeoxycorticosterone) represent the first "rationally, designed, enzyme-activated inhibitors of aromatase (11:17-34)." The compounds act as pseudo-substrates for the targeted enzymes. Journal of Steroid Biochemistry and Molecular Biology. A number of different organs produce the various steroid hormones.The progestagens, for instance, are produced by the corpus luteum. This enzyme "inserts oxygen into the C-H bonds of the C-19 methyl during the first two oxidative steps to producethe 19-carboxyaldehyde derivative (11:17-34)." The androgens and estrogensstimulate the development of male and female secondary sex characteristicsand sexual behavior patterns, respectively (12:443-449). Estrogens alsohave an important role in the ovarian cycle. Steroids. This compound, however, does not have any biologicactivity. Aoyama, T.; Korzekwa, K.; Nagata, K.; Adesnik, M.; Reiss, A.; Lapenson, D. This sequence ofevents is similar to the hydroxylation of phenylalanine as follows: RH +O2 + NADPH + H+ -> ROH + H2O + NADP+ (14:474-482). Guengerich, F. This compound is then photolyzed by ultraviolet light topre-vitamin D3. Freeman and Company; 1981.15. Journal of Steroid Biochemistry and Molecular Biology. L.; Halpert, J. It is generally considered that thegreater concentration of this protein in the gonads--as compared to theadrenal glands--results in the production of androgens in the testes andcortisol in the adrenal glands (8:527-532). Theglucocorticoids promote gluconeogenesis and the formation of glycogen. Stryer, L. Hormones and Behavior. First, pregnenolone's 3-hydroxyl group is oxidized to a 3-keto group. This superfamily, known as the cytochromeP45 enzymes, all possess a heme prosthetic group (9:4419). The regio- and stereoselective transformation of structurallycomplex substrates to yield chiral products usually requires sophisticatedand time-consuming chemical techniques. Kubli-Garfias, C. Thishormone acts in a synergistic manner with parathyroid hormone to increaseserum Ca2+ (15:1145-1146). The transformation of pregnenolone to progesterone involves twodifferent steps. Biochemical Society Transactions. This deoxycorticosterone is thenhydroxylated again at C-11. L.; Holbert, G. Enzyme-activated inhibitors of steroidal hydroxylases. Although the hydroxylation of estrogens may involve three differenthydroxylating systems (i.e., peroxidases, tyrosinases, and "unspecific"monooxygenases), the "classic estrogen 2-/4-hydroxylase" appears to be acytochrome P45 (3:2163-2169). These proteins occur in a diverse array of organisms. Inaddition, the glucocorticoids and mineralocorticoids are synthesized by theadrenal cortex. The reduced form of theenzyme them activates O2 (14:474-482). Thesehormones are all somewhat similar in structure: For example, all containthe "four-ring structure of the sterol nucleus (15:656-657). First, cholesterol's C-2 and C-22 atoms are hydroxylated to give2 (,22-dihydroxycholesterol. 33:4419-4424; 1994.1 . Thecompounds thus produced are then either reexcreted into the bile ortransported to the kidney for urinary excretion (5:59-72). 123:151-159; 1993. This single protein--cytochrome P45 C21scc--determineswhether the cholesterol substrate becomes a glucocorticoid or analdosterone. For instance,P45 IIB1 and P45 IIB2 are responsible for catalyzing 16( and 16ßhydroxylations of androgens, respectively. 21:1 77-1 8 ; 1993, November.14. 4. In 1925, David Keilindiscovered that the proteins alternate between a reduced ferrous state andan oxidized ferric state during the transport of a single electron (14:313-314). 52:17-34; 1995.12. For the most part, hydroxylation serves to increase thepolarity of the rather hydrophobic steroids. In addition,progesterone is also required for the maintenance of pregnancy. 163 (6 Part 2):2159-2163; 199 , December. Many microorganisms are capable of steroidhydroxylation. In addition to various organs of the body, steroid hydroxylation canbe accomplished by certain microorganisms. The pharmacologicpotential of these compounds may be altered through hydroxylation. Thus,progesterone is converted to 11-deoxycorticosterone, corticosterone, andthen to aldosterone. By increasing their aqueoussolubility, the hydroxyl functionalities may make certain substancesbioactive.
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