cis-Platinum: subcellular distribution and binding to cytosolic ligands

Abstract

In the present experiments the tissue uptake and subcellular distribution of Pt were measured in the liver and kidney of rats injected intraperitonially with 5 mg cis-diamminedichloroplatinum (cis-DPP)/kg. The binding of Pt to cytosolic ligands was also investigated. In both the liver and kidney Pt concentration was maximal within 24 hr following cis-DDP injection. Thereafter the clearance was bimodal with a rapid phase of about 48 hr (with 60-70% clearance) followed by a slow incomplete phase. In the kidney relatively high concentrations of Pt were measured in the microsomal, lysosomal and mitochondrial fractions. But in the liver the higher levels were found in the microsomal and nuclear fractions. On average 62% (kidney) and 89% (liver) of the cellular Pt were localized in the cytosol. At 24 hr following cis-DDP injection, about 52% of cytosolic Pt was present as low molecular weight species (molecular weight less than 1000) and the remainder as protein-bound. About 25% was bound to a metallothionein-like protein in the liver as well as the kidneys. It is suggested that the high localization of cellular Pt in the cytosol and the presence of a high proportion as non-protein bound species may be important factors in relation to the therapeutic as well as the toxic effects of cis-DDP.