Membrane steroid-binding protein

Genetic variations within the UGT1A1 gene have also been associated with the development of certain drug toxicities . The UGT1A1 *28 variant , the same allele behind many cases of Gilbert syndrome , has been associated with an increased risk for neutropenia in patients receiving the chemotherapeutic drug irinotecan , [17] [18] and the . Food and Drug Administration recommends on the irinotecan drug label that patients with the *28/*28 genotype receive a lower starting dose of the drug. [19] The *28 allele has also shown associations with an increased risk for developing diarrhea in patients receiving irinotecan . [17] [18] The UGT1A1 *6 variant , more common in Asian populations than the *28 variant , has also shown associations with the development of irinotecan toxicities. Patients who are heterozygous or homozygous for the *6 allele may have a higher risk for developing neutropenia and diarrhea as compared to those with the UGT1A1 *1/*1 genotype . [17] [18]

Congenital adrenal hyperplasia (CAH) is an autosomal recessive disorder, and occurs in approximately 1 in 15000 births globally. [17] [18] There are multiple forms of CAH, broken down into classical and nonclassical forms based on the amount of function retained. The classical forms include salt-wasting (SW), and simple-viralizing (SV). Mutations that interfere with the active site—the heme group or residues involved in substrate binding—result in a complete loss of enzymatic activity, the salt-wasting type. [19] Cortisol and aldosterone deficits are associated with life-threatening salt-loss (hence salt-wasting), as the steroids play roles in regulating sodium homeostasis . Retaining minimal enzyme activity, the simple-viralizing type is associated with mutations in conserved hydrophobic regions or near the transmembrane domain. Simple viralizing CAH patients maintain adequate sodium homeostasis, but exhibit other phenotypical symptoms shared by SW, including accelerated growth in childhood and ambiguous genitalia in female neonates. Nonclassical forms retain 20-60% of hydroxylase function—this form is associated with normal cortisol expression, but an excess of androgens post-puberty. [20] [21]

Protein S can bind to negatively charged phospholipids via the carboxylated Gla domain. This property allows Protein S to function in the removal of cells which are undergoing apoptosis . Apoptosis is a form of cell death that is used by the body to remove unwanted or damaged cells from tissues. Cells, which are apoptotic (. in the process of apoptosis ), no longer actively manage the distribution of phospholipids in their outer membrane and hence begin to display negatively charged phospholipids, such as phosphatidyl serine, on the cell surface. In healthy cells, an ATP ( Adenosine triphosphate )-dependent enzyme removes these from the outer leaflet of the cell membrane. These negatively charged phospholipids are recognized by phagocytes such as macrophages . Protein S can bind to the negatively charged phospholipids and function as a bridging molecule between the apoptotic cell and the phagocyte. The bridging property of Protein S enhances the phagocytosis of the apoptotic cell, allowing it to be removed 'cleanly' without any symptoms of tissue damage such as inflammation occurring.

Because steroids are lipophilic, they diffuse easily through the cell membranes, and therefore have a very large distribution volume. In their target tissues, steroids are concentrated by an uptake mechanism which relies on their binding to intracellular proteins (or " receptors ", see below). High concentration of steroids are also found in adipose tissue, although this is not a target for hormone action. In the human male, adipose tissue contains aromatase activity, and seems to be the main source of androgen-derived estrogens found in the circulation. But most of the peripheral metabolism occurs in the liver and to some extent in the kidneys, which are the major sites of hormone inactivation and elimination, or catabolism (see below).

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Membrane steroid-binding protein

membrane steroid-binding protein

Because steroids are lipophilic, they diffuse easily through the cell membranes, and therefore have a very large distribution volume. In their target tissues, steroids are concentrated by an uptake mechanism which relies on their binding to intracellular proteins (or " receptors ", see below). High concentration of steroids are also found in adipose tissue, although this is not a target for hormone action. In the human male, adipose tissue contains aromatase activity, and seems to be the main source of androgen-derived estrogens found in the circulation. But most of the peripheral metabolism occurs in the liver and to some extent in the kidneys, which are the major sites of hormone inactivation and elimination, or catabolism (see below).

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