Steroid hormone conjugates sulfates

MRP1 (ABCC1) Glucuronides and sulfate conjugates of steroid hormones and bile salts, colchicine, doxorubicin, daunorubicin, epirubicin, folate, irinotecan, methotrexate, pacitaxel, vinblastine, vincristine, and others... 

Bilirubin is nonpolar and would persist in cells (eg, bound to lipids) if not rendered water-soluble. Hepatocytes convert bilirubin to a polar form, which is readily excreted in the bile, by adding glucuronic acid molecules to it. This process is called conjugation and can employ polar molecules other than glucuronic acid (eg, sulfate). Many steroid hormones and drugs are also... 

Conjugations can also be brought about by sulfotransferases (SULTs) and glutathi-one-S-transferases (GSTs), both of which exist in a number of isoenzymic forms. Amines and alcohols are sulfate acceptors and SULTs are important in steroid hormone and catecholamine metabolism and like the UGTs require the sulfate to be activated prior to its incorporation into the target molecule (Figure 6.32). In this case, sulfate is activated at the expense of two molecules of ATP to form the final sulfate carrier PAPS O -phosphoadenosine-S -phosphosulfate). 

The steroid hormones are mainly inactivated in the liver, where they are either reduced or further hydroxylated and then conjugated with glucuronic acid or sulfate for excretion (see p. 316). The reduction reactions attack 0X0 groups and the double bond in ring A. A combination of several inactivation reactions gives rise to many different steroid metabolites that have lost most of their hormonal activity. Finally, they are excreted with the urine and also partly via the bile. Evidence of steroids and steroid metabolites in the urine is used to investigate the hormone metabolism. 

Sulfotransferases (SULTs) are important for the metabolism of a number of drugs, neurotransmitters, and hormones, especially the steroid hormones. The cosubstrate for these reactions is 3 -phosphoadenosine 5 -phosphosulfate (PAPS) (Fig. 4.1). Like the aforementioned enzymes, sulfate conjugation typically renders the compound inactive and more water soluble. However, this process can also result in the activation of certain compounds, such as the antihypertensive minoxidil and several of the steroid hormones. Seven SULT isoforms identified in humans, including SULTs lAl to 1A3, possess activity toward phenolic substrates such as dopamine, estradiol, and acetaminophen. SULTIBI possesses activity toward such endogenous substrates as dopamine and triiodothyronine. SULTIEI has substantial activity toward steroid hormones, especially estradiol and dehydroepiandrosterone, and toward the anti-... 

Approximately 50% of a dose of mestranol is de-methylated to form ethinyl estradiol. Ethinyl estradiol also can be deethinylated. Subsequently, the metabolism of these two synthetic estrogens proceeds by means of the same pathways as the natural steroid hormones. The principal metabolites of mestranol and ethinyl estradiol are hydroxylated derivatives that are conjugated with either glucuronic acid or sulfate. The synthetic steroid estrogens, in contrast to the natural estrogens, are excreted primarily in the feces. 

Steroid hormones are generally converted into inactive metaboic excretion products in the liver. Reactions include reduction of unsaturated bonds and the introduction of additional hydroxyl groups. The) resulting structures are made more soluble by conjugation with curonic acid or sulfate (from PAPS, see p. 160). Approximate ) twenty to thirty percent of these metabolites are secreted into the bile and then excreted in the feces, whereas the remainder ae t released into the blood and filtered from the plasma in the kidney, passing into the urine. These conjugated metabolites are fairb1 water-soluble and do not need protein carriers. 

Most hormones have a half-life in the blood of only a few minutes because they are cleared or metabolized very rapidly. The rapid degradation of hormones allows target cells to respond transiently. Polypeptide hormones are removed from the circulation by serum and cell surface proteases, by endocytosis followed by lysosomal degradation, and by glomerular filtration in the kidney. Steroid hormones are taken up by the liver and metabolized to inactive forms, which are excreted into the bile duct or back into the blood for removal by the kidneys. Catecholamines are metaboli-cally inactivated by O-methylation, by deamination, and by conjugation with sulfate or glucuronic acid. 

SULT 2A and 2B sulfotransferase subfamily members sulfate the 3P-hydroxyl group of a variety of steroid hormones. Dehydroepiandrosterone (DHEA) is the prototypical substrate for the SULT 2 enzymes. However, other hydroxysteroids such as testosterone and its phase I hydroxylated derivatives are substrates for these enzymes. The SULT 2 sulfotransferases also are responsible for the sulfate conjugation of a variety of alcohols and xenobiotics that have undergone phase I hydro-xylation, including the polycyclic aromatic hydrocarbons (PAHs). The SULT 2 enzymes exhibit different patterns of tissue expression. SULT 2A1 is expressed primarily in the adrenal cortex, brain, liver, and intestine, while SULT 2B1 is expressed in the prostate, placenta, and trachea. 

Cortisol, a steroid hormone, is reduced and conjugated with gluc-uronide or sulfate and excreted in the urine and the feces. 

OATP transporters, SLCOICI, SLC02B1, SLC03A1, SLC04A1, and SLC04C1 have been found in the jejunum, and also in the colon, with the exception of SLC03A1 [3[. OATP-B (SLC02B1) accepts bile salts, as well as pravastatin (XIII) and sulfate conjugates of steroid hormones, and is localized in the apical membrane of enterocytes [32]. 

Mammalian cells lack the ability to completely degrade steroid compounds. As a result, most become conjugated through their hydroxyl groups to glucuronate or sulfate and are eliminated in the urine. This is why the urine of athletes is used to test for illegal steroid hormone use. 

The conjugation and inactivation pathways are similar to those used by the hver to inactivate many of its own metabolic waste products. These pathways are intimately related to the biosynthetic cascades that exist in the liver. The liver can synthesize the precursors that are required for conjugation and inactivation reactions from other compounds. For example, sulfation is used by the liver to clear steroid hormones from the circulation. The sulfate used for this purpose can be obtained from the degradation of cysteine or methionine. 

Cholesterol sulfate occurs in bovine adrenal glands (Drayer et ai, 1964). This fact raises the possibility that the conjugate may represent an active form of cholesterol in metabolic processes other than those concerned with steroid hormone biosynthesis. Isolation of the sodium and pyridinium salts of cholesterol sulfate and recording of their infrared spectra led to the identification of these compounds. 

Steroid hormones can be inactivated by conjugation and degradation. Conjugation involves the formation of either glucuronides or aryl sulfates. Steroids are conjugated with glucuronic acid in the presence of a liver microsomal enzyme and UDP-glucuronic acid. 

According to the classical view of metabolism the hormones are synthesized as free steroids in endocrine tissues and prepared for excretion in urine by peripheral metabolism and conjugation. This view had to be modified upon the isolation of dehydroepiandrosterone sulfate from adrenal tumor [307]. Thus dehydroepiandrosterone sulfate, a steroid conjugate, was shown to be secreted by the adrenal tissue. Isotopic methods also pointed in the same direction. Lieberman et al. [304], using... 

Technically, acid hydrolysis is often preferred (except for acid-labile hormones), because the process offers simplicity and speed and usually results in complete hydrolysis regardless of the nature of conjugates. Enzymatic hydrolysis requires special attention to factors such as optimal concentration and type of enzyme, pH, temperature, and duration of incubation. In addition, the possible presence of enzyme inhibitors, which vary in amount and nature with different specimens, may affect the completeness of hydrolysis. In spite of potential problems, enzymatic hydrolysis is used for plasma analysis of steroids that are labile in strong acid solution (e.g., pregnanetriol and corticosteroids), and because it prevents interference from substances that are produced by acid hydrolysis. Enzymatic hydrolysis, for example, has been used successfully to determme the urine concentration of estrone and the plasma concentration of estrone sulfate in postmenopausal women. 

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