SUCCINYLACETONE, A POTENT INHIBITOR OF HEME-BIOSYNTHESIS - EFFECT ON CELL-GROWTH, HEME CONTENT AND DELTA-AMINOLEVULINIC-ACID DEHYDRATASE ACTIVITY OF MALIGNANT MURINE ERYTHROLEUKEMIA-CELLS

4,6-Dioxoheptanoic acid (succinylacetone, SA) [a metabolite excreted in patients with hereditary tyrosinemia] was examined with regard to its ability to inhibit the 2nd enzyme of the heme pathway, .delta.-aminoleuvulinic acid (ALA) dehydratase, lower the heme concentration and inhibit cell growth of murine erythroleukemia (MEL) cells in culture. SA profoundly inhibited ALA dehydratase in broken cell preparations at concentrations as low as 10-7 M. The stimulation of Hb production by DMSO [dimethylsulfoxide] and butyrate in MEL cells was inhibited by the addition of SA to the cell medium. When 1 mM SA was added to the medium, there was a profound inhibition of ALA dehydratase activity, and the heme concentration of cells declined progressively with each cell division. Cell growth was markedly inhibited after 2 cell divisions.