Metabolism of somatostatin and its analogues by the liver

The rate of degradation of 125I-labelled [Tyr11]somatostatin by isolated rat hepatocytes was similar to that of unlabelled somatostatin. Reaction was dependent upon cell concentration and temperature, being rapid at 37 degrees C and negligible at 0 degrees C. The apparent Km for the overall degradative process was approximately the same for degradation by hepatocytes and by partially-purified liver plasma membranes. Extracellular breakdown of somatostatin, by proteases released from cells into the incubation medium, represented less than 10% of the cell-associated degradation. Homogenization of hepatocytes resulted in a 10--20-fold increase in the degrading ability of the cells. After incubation of 125I-labelled [Tyr11]somatostatin and 125I-labelled [Tyr1]somatostatin with hepatocytes, 125I-labelled tyrosine was the major radioactive product identified in the incubation medium. The rate of release of 125I-labelled tyrosine from the labelled [Tyr1]analogue was approximately 11 times greater than from the labelled [Tyr11] analogue. 125I-labelled [Tyr11]somatostatin bound to the cells in a non-saturable manner and approx. 70% of the cell-associated radioactivity could be dissociated by dilute acid. The rate of degradation of somatostatin was unchanged by reagents that inhibit the internalisation and lysosomal degradation of polypeptides by cell suspensions but was reduced by reagents that inhibit sulphydryl-dependent proteases. It is proposed that plasma-membrane associated proteolysis, involving both endo- and exopeptidases may represent the predominant degradative pathway of somatostatin in vivo.