METABOLISM OF DOXORUBICIN IN LONG-TERM BONE MARROW CULTURES AND SR-4987 STROMAL ESTABLISHED CELL LINE

Abstract

The metabolism of doxorubicin was studied in murine long-term bone marrow cultures (LTBMC) and in SR-4987 established stromal cells in comparison with primary cultures of murine and rat hepatocytes. The toxicity of metabolites was verified by testing their effects on the clonogenicity of granulo-macrophage progenitors. Metabolic activity was compared in subcellular fractions of SR-4987 cells and murine hepatocytes. Doxorubicin was transformed in long-term bone marrow cultures, SR-4987 cells and murine/rat hepatocytes to less toxic metabolites: 13-OH doxorubicin and a less polar metabolite which were non-toxic on granulo-macrophage progenitors. Among the hemopoietic compartments, stromal cells were responsible for the biotransformation of doxorubicin. The capability of the SR-4987 established stromal cell line to metabolize doxorubicin was higher than that of primary cultures of hepatocytes and bone marrow, and the highest activity was concentrated in the microsomes. These results suggest that in vitro models using primary cell cultures and established cell lines could be a useful tool for investigating the mechanisms underlying detoxification in the bone marrow stromal population.