Cholecalciferol, calcidiol, calcitriol, and 24-hydroxycalcidiol are all transported bound to the same plasma binding protein - Gc-globulin, also known as the group-specific component or transcalciferin. There are three major forms of Gc-globulin, with differing primary structures, and a number of minor variants of each because of differences in postsynthetic glycosylation. There is considerable polymorphism among human populations; because of this, Gc-globulin has been investigated both for its interest in population genetics and also its potential value in forensic medicine. All the variants bind vitamin D and its metabolites with similar affinity. It is noteworthy that the absence of Gc-protein has never been detected, suggesting that a deletion of this protein may be fatal. Cholecalciferol is also transported in plasma lipoproteins, so that about 60% is normally bound to Gc-globulin and 40% to lipoproteins. It is only that fraction bound to lipoproteins that is taken up by the liver for 25-hydroxylation (Haddad et al., 1988). In addition to its role in the plasma transport of vitamin D, and control over tissue uptake, Gc-globulin represents the major storage site for the vitamin, mainly as calcidiol.
The plasma binding protein has a higher affinity for calcidiol and 24-hydroxycalcidiol than for calcitriol or cholecalciferol. The plasma concentration of Gc-globulin is about 6 mmol per L - considerably higher than the concentrations of other hormone binding proteins, such as thyroxine binding globulin (300 ^mol per L), cortisol binding globulin (800 ^mol per L), or sex hormone binding globulin (40 ^mol per L in males and 80 ^mol per L in females) and far in excess of circulating vitamin D. As a result of this, whereas the other hormone binding globulins are about 50% saturated under normal conditions, the vitamin D binding protein is only about 2% saturated. This means that changes in the circulating concentration of the protein are unlikely to have any significant effect on the small proportion of vitamin D metabolites that is free, rather than protein-bound. Again, unlike other hormone binding globulins, the plasma concentration of Gc-globulin is not affected by vitamin D status or other factors that affect calcium homeostasis and vitamin D metabolism (Cooke and Haddad, 1989; Haddad, 1995).
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