Metabolism of the complex monofluorophosphate-alpha 2-macroglobulin in therat

Sodium monofluorophosphate (MFP) is a drug used in the treatment of primary osteoporosis. Following the intake of MFP, a small fraction of the drug is absorbed intact and forms a complex with alpha 2-macroglobulin (MFP-alpha 2M) inactivating the antiproteasic activity of the globulin. The complex ha s been shown to occur in the serum of rats and human being. This paper repo rts data on the metabolism of this complex in the rat. In vitro experiments showed that liver and bone tissue remove MFP-alpha 2M from the incubation medium. When the experiments were pursued beyond the time needed to reduce the complex concentration to very low levels, fluorine (F) reappears in the medium in two forms: bound to low molecular weight macromolecule/s (2,200 +/- 600 Ca) and as ionic F. Concentrations of these F fractions increase wh ile that of the complex decreases as a function of time. In vitro, uptake o f the complex by liver or bone tissue was not affected by the presence of c olchicine or methylamine. These drugs, however, inhibited intracellular met abolism of the complex, as indicated by the impairment of the return of F s pecies to the extracellular space and the increase in F content of the tiss ue. The cellular receptors responsible for the uptake of the complex in liv er and bone are insensitive to low concentration of calcium and inhibited b y polyinosinic acid[5']. These features characterize the "scavenger" recept or, one of the two receptor types known to remove inactive alpha 2M from th e circulation. Injection of polyinosinic acid [5'] to living rats also hind ered the disappearance of the complex from serum. It is concluded that the metabolism of the MFP-alpha 2M complex involves binding to receptors, uptak e by cells, lysosomal degradation and return of F bound to low molecular we ight macromolecule/s to the extracellular space. It is assumed, however, th at inorganic F is the final product of lysosomal hydrolysis of the protein moiety.