Introduction The presence of corticosteroid-binding globulin (CBG) in plasma was detected about 30 yr ago, and of sex hormone-binding globulin (SHBG) about 20 yr ago. In the interval since their discovery, sophisticated binding and RIAs have been devised for their measurement; their concentrations in plasma and other biological fluids, from milk to saliva, have been measured in myriad clinical conditions in humans, and numerous experimental ones in animals; their phyletic distribution has been examined; they have been isolated and their complementary DNAs (cDNAs) cloned; their binding specificities for steroids have been examined in heroic detail; hormonal and drug influences on their plasma concentration in vivo, and their secretion by liver cells in vitro, have been widely explored; they have been the subject of two long, splendid monographs (1, 2) and many shorter reviews (3–11) [wherein the original citations for the first part of this sentence may be found]—and yet we still have not come to a consens...

The functions of corticosteroid-binding globulin and sex hormone-binding globulin: recent advances.

I Introduction AVARIETY of extracellular binding proteins enhance the solubility of steroid hormones in biological fluids and facilitate their transport from steroidogenic tissues to target cells (1) In mammals, albumin is quantitatively the most important of these proteins and provides a large reservoir of loosely bound hormone that may be released within some target tissues (2) Two albumin-related proteins, vitamin D binding protein and α-fetoprotein, also appear to have arisen by duplication of a common ancestral gene (3) and are characterized by higher affinities and specificities for steroid ligands The molecular composition and structure of the vitamin D binding protein have already been described in detail (4), and this review will concentrate on the molecular properties of two other biologically important classes of extracellular steroid binding proteins: corticosteroid binding globulin (CBG) and the sex-steroid binding proteins; sex hormone binding globulin (SHBG) and androgen binding protein

Molecular properties of corticosteroid binding globulin and the sex-steroid binding proteins

In human blood, cortisol is transported by a plasma protein known as corticosteroid-binding globulin (CBG). As anticipated from primary structure comparisons of CBG and alpha 1-proteinase inhibitor (A1-PI), CBG acts as a substrate for neutrophil elastase. However, unlike A1-PI, CBG does not alter the activity of this enzyme, but is cleaved by it at a single location close to its carboxy-terminus, and this reduces its molecular size by 5 kDa with the concomitant release of more than 80% of CBG-bound cortisol. Three small molecular size fragments are detected after elastase cleavage, and carbohydrate analysis of these fragments suggests that they represent the same polypeptide fragment which has been differentially glycosylated. To assess the biological significance of these observations, CBG was incubated with either mononuclear cells or granulocytes obtained from patients with acute inflammation (sepsis) and from a normal volunteer. Only granulocytes from septic patients reduced the mol wt of CBG by about 5 kDa and destroyed its steroid-binding activity. Preincubation with A1-PI prevented this, which demonstrates that neutrophil elastase plays a key role in this event. These results suggest a physiological role for CBG in the delivery of cortisol to sites of inflammation.

A Role for Corticosteroid-Binding Globulin in Delivery of Cortisol to Activated Neutrophils

The plasma steroid-binding proteins, sex hormone-binding globulin (SHBG) and corticosteroid-binding globulin (CBG), transport steroid hormones in the blood and regulate their access to target tissues. Recent biochemical and molecular analyses of these proteins and their genes, and studies of their biosynthesis and localization in the liver and other tissues during development, have led to the realization that CBG and SHBG function in much more sophisticated ways. In particular, the presence of plasma membrane binding sites for both CBG and SHBG on steroid target cells, and evidence for interactions between CBG and specific proteinases at sites of inflammation or tissue remodeling, suggest that these proteins control steroid hormone bioavailability and/or action in a highly selective or targeted fashion. This new information should not only serve to extend our understanding of the basis of steroid-hormone dependent diseases, but may influence the design of steroid hormone agonists and antagonist of therapeutic potential.

https://www.cell.com/trends/endocrinology-metabolism/pdf/1043-2760(95)00162-X.pdf

Potential functions of plasma steroid-binding proteins.

Despite over 20 years of research, the functions of ABP and SHBG remain elusive. The major reason for this lack of knowledge has been the unavailability of natural mutants with clinical defects for study. There is strong evidence that these binding proteins do act to modulate the gene regulatory actions of nuclear sex steroid receptors by controlling the availability of androgens and estrogens. In plasma, SHBG controls the metabolic clearance rate of sex steroids. In addition there is strong evidence that they have a much broader function. The identification of plasma membrane receptors in target tissues and the finding of homologous domains in several developmental proteins support other functions. Moreover, other experiments suggest the proteins may actually be hormones or growth factors. These findings are not compatible with a model that has the proteins only regulating free steroid hormone levels. Obviously, much more experimentation will be necessary to reveal the functions of ABP and SHBG. The recent discoveries have offered several clues to their functions and open new routes for study. These experiments, coupled with newly developed techniques, such as gene knockout by homologous recombination, make one optimistic that the functions of these unique proteins will be deciphered in the near future.

I.V. Matveentseva

Papers

Study of the carbohydrate moiety of human serum sex hormone-binding globulin

Isolation and characterization of glycopeptides of human transcortin.