In Vitro Uptake and Subcellular Distribution of the Cardiotoxin [3H]Adriamycin in Mouse Ventricle Slices

Abstract

Adriamycin (ADR) is a drug with relatively selective cardiotoxicity. The present study was designed to investigate its distribution into heart subcellular components and correlate such distribution with proposed loci of cardiotoxicity. Uptake of [3H]ADR by mouse ventricular slices was linear for 30 min and plateaued thereafter. The uptake was temperature dependent, being linear from 0° to 45°C. Uptake was also linear over an ADR concentration range of 0.59–8.85 times 10-4 M and increased with wet weight of tissue (25–110 mg). Preincubation with metabolic inhibitors (10-4 M; iodoacetamide and 2,4-dinitrophenol) or 100% N2 failed to affect uptake. Subcellular distribution studies demonstrated preferential localization in nuclei, mitochondria, microsome, and soluble fractions (dpm/μmg protein) in diminishing order, respectively. Therefore, the uptake of ADR by mouse ventricular slices does not involve an energy-dependent transport process and its subcellular localization corresponds with proposed loci of cardiotoxicity.