Steroid hormone inactivation

Phytoestrogens may also modulate the concentration of endogenous steroid hormones by binding to and inactivating the enzymes involved in their biosynthesis and metabolism. 

Sustained- and controlled-release devices for drug delivery in the vaginal and uterine areas are most often for the delivery of contraceptive steroid hormones. The advantages in administration by this route—prolonged release, minimal systemic side effects, and an increase in bioavailability—allow for less total drug than with an oral dose. First-pass metabolism that inactivates many steroid hormones can be avoided [183,184],... 

With the exception of two dehydrogenases, all of the steroidogenic enzymes belong to the cytochrome P-450 (abbreviated as CYP) family of enzymes. The CYP enzymes are often involved with redox or hydroxylation reactions, and are also found in the liver where they are key players in biotransformation reactions (see Section 6.4). Different members of the CYP family are therefore involved with both synthesis in adrenal and gonads and hepatic inactivation of steroid hormones. 

In the liver s hepatocytes, the proportion represented by the sER is particularly high. It contains enzymes that catalyze so-called biotransformations. These are reactions in which apolar foreign substances, as well as endogenous substances—e. g., steroid hormones—are chemically altered in order to inactivate them and/or prepare them for conjugation with polar substances (phase I reactions see p. 316). Numerous cytochrome P450 enzymes are involved in these conversions (see p. 318) and can therefore be regarded as the major molecules of the sER. 

Biotransformation. Steroid hormones and bilirubin, as well as drugs, ethanol, and other xenobiotics are taken up by the liver and inactivated and converted into highly polar metabolites by conversion reactions (see p. 316). 

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. 

Inactivated steroid hormones are conjugated to glucuronic acid prior to excretion in the urine. 

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. 

Secondary hyperaldosteronism Fluid retention is also promoted by elevated levels of circulating aldosterone. This secondary hyperaldosteronism results from the decreased ability of the liver to inactivate the steroid hormone and leads to increased Na+ and water reabsorption, increased vascular volume, and exacerbation of fluid accumulation (see Figure 23.3). 

As discussed in Section 9.3.3, pyridoxal phosphate is involved in the regulation of gene expression, terminating the responses to steroid hormones and inactivating some tissue-specific transcription factors. There is decreased synthesis of pancreatic digestive enzymes in vitamin Bg deficiency, although the synthesis of other pancreatic proteins is unaffected (Dubick et al., 1995). 

Steroid hormones (as well as the thyroid hormones, 1,25-dihydroxycholecalciferol, and retinoic acid cross) the cell membrane and bind to intracellular receptors. Ultimately, the hormone-receptor complex binds to DNA and activates or inactivates genes, which produce proteins that have physiologic effects. 

Our laboratory is concerned with targeting potential insecticides that disrupt normal development and metamorphosis in insects. Juvenile hormones (JHs), acting in concert with the steroid hormone ecdysone, are believed to control the timing of the larval-larval molts, larval-pupal and pupal-adult transformations of the insects. It has been demonstrated that the events leading to pupation are initiated by reduction of the JH titer in the hemolymph. In addition to a cessation of biosynthesis, this reduction in JH titer is controlled by degradative metabolism (16,17). Hydrolysis of the epoxide and ester functionalities present in active JH are two routes of degradation and subsequent inactivation of JH (18). The primary route of JH metabolism in the hemolymph of last stadium lepidopterous larvae is ester hydrolysis, and it is catalyzed by the enzyme juvenile hormone esterase (JHE). JHE has been shown to... 

Another effect of glucagon binding to liver cells is the inactivation of the glycolytic enzyme pyruvate kinase. (Protein kinase C, an enzyme activated by cAMP, converts pyruvate kinase to its inactive phosphorylated conformation.) Hormones also influence gluconeogenesis by altering enzyme synthesis. For example, the synthesis of gluconeogenic enzymes is stimulated by cortisol (a steroid hormone... 

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. 

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