Clearance mechanism of prostate specific antigen and its complexes with α2-macroglobulin and α1-antichymotrypsin

Purpose: To investigate the rate of elimination of prostate specific antigen (PSA) and its complexes with human alpha 2-macroglobulin (alpha 2-M) and alpha 1-antichymotrypsin (ACT) and to elucidate the role of the alpha 2-macroglobulin-receptor/low density lipoprotein receptor-related protein ((alpha 2-M-R/LRP) in the clearance mechanism. Materials and Methods: PSA and complexes of PSA with alpha 2-M and ACT were prepared and radiolabeled with [I-125]Na (Amersham, Braunschweig, Germany). Radiolabeled proteins were injected into rats and the elimination of radioactivity from circulation was measured by gamma-counting of 20 mu L aliquots over time. After 30 minutes different organs were removed and the total radioactivity was counted. The elimination rate and distribution of PSA and PSA-complexes was studied in the absence and presence of an excess of transformed alpha 2-M. Results: Radiolabeled PSA is rapidly eliminated from circulation with an initial half-life of 6.4 +/- 2.1 minutes mainly due to extraction by the liver and kidney. The clearance is slightly inhibited by transformed alpha 2-M. PSA-alpha 2-M is solely eliminated by the liver with a half-life of 6.7 +/- 1 minutes. Uptake by the liver is competitively inhibited by transformed (alpha 2-M. PSA-ACT is eliminated by the liver and kidney with an initial half-life of 3.51 +/- 1.1 minutes. Transformed alpha 2-M failed to inhibit the clearance of PSA-ACT. Conclusions: Free PSA and PSA-inhibitor complexes are removed from the circulation by different clearance mechanisms. The sites of metabolism of the different forms of PSA are different but include liver and kidney as main organs for uptake. There are indications that alpha 2-M-R/LRP is involved in PSA elimination. Thus, factors which modulate the receptor function and expression as well as the concentration of its natural ligands may interfere with the steady state concentrations of different PSA forms in blood.