Acute-Phase Proteins: Alpha -1- Acid Glycoprotein

Acute-phase proteins are proteins whose plasma concentrations increase in response to inflammation. The variability in protein plasma levels, and following impact on drug binding extent, cause modifications in the mode of drug action, distribution, disposition and elimination. One of the most important acute phase proteins is a1-acid glycoprotein (AAG or AGP), principal binding protein for basic drugs. Although plasma concentration of AAG is much lower than that of albumin, AAG can become the major drug binding macromolecule in plasma with significant clinical implications. Moreover AAG is involved in drug-drug interactions, especially in the displacement of drugs and endogenous substances from their binding sites, with important pharmacokinetic and clinical consequences. AAG is an acidic glycoprotein of about 41 kDa , a single chain of 183 amino acids, the tertiary structure of which partially resembles those of cellular beta 2-agonist receptors. The carbohydrate content (glycans) represents 45% of its molecular weight. The biological function of AGP remains unknown; however, a number of activities of possible physiological significance, such as various immunomodulating effects, have been described. The immunomodulatory as well as the binding activities of AGP have been shown to be mostly dependent on its carbohydrate composition. AAG is one of the plasma acute phase proteins synthesized by the liver and is mainly secreted by hepatocytes and its serum concentration increases in response to systemic tissue injury, inflammation, infection or cancer. Human alpha1-acid glycoprotein displays genetic polymorphism. AGP of most individuals exists as a mixture of two or three main genetic variants (i.e. A variant and F1 and/or S variants). Concerning native human AGP composition, the relative occurrence of the three main phenotypes in the population was found to be about 50% for F1+S+A, 35% for F1+A and 15% for S+A. Different drug binding properties of the two main genetic products (F1-S and A variants) have been demonstrated. Various drug molecules have different selectivity in binding affinities for the genetic variants, ranging from the lack of selectivity to the total preference of one of the variants. In binding competition experiments performed by dialysis, radioactive imipramine and warfarin were chosen as high-affinity selective marker ligands for the A variant and the F1-S