Effect of Tri-O-cresyl phosphate (TOCP) on proteolytic enzyme activities in mouse liver in vivo

To develop a clearer understanding of the biochemical mechanisms of toxicity in higher animals, we determined the effect of four sublethal dosages (0.25 to 1.0 g/Kg) of organophosphate (OP), and of tri-ortho-cresyl phosphate (TOCP) on the activities of a representative range of cytoplasmic and lysosomal proteolytic enzymes in mouse liver in vivo. Administration of the lowest sublethal dosage of TOCP (0.25g/1Kg, 24 hours) resulted in significant inhibition (10 to 30% of control activity) of the cytoplasmic proteases tripeptidyl aminopeptidase and proline endopeptidase only. An increasing dosage of TOCP (1g/Kg for 7 days) resulted in significant inhibition (10 to 50% of control activity) of the cytoplasmic proteases alanyl aminopeptidase, leucyl aminopeptidase, tripeptidyl aminopeptidase, and proline endopeptidase, as well as the lysosomal proteases dipeptidyl aminopeptidase I and cathepsins B, D, and L. The activities of the cytoplasmic proteases arginyl aminopeptidase and dipeptidyl aminopeptidase IV, and of lysosomal proteases dipeptidyl aminopeptidase II and cathepsin H were not significantly altered following TOCP administration at this higher dosage. All of the above proteases are involved in the general process of intracellular protein turnover (common to all tissues), and may also have more specialized functions such as the processing of physiologically active hormonal peptides, and the processing of antigenic proteins in the immune response. Data obtained in the present study suggest that inhibition of the above enzymes by OP such as TOCP may represent a previously unrecognized toxicity hazard induced by the latter compound in higher animals.