In Vitro Inhibition of Granulopoiesis by 4‐Amino‐4′‐Hydroxylaminodiphenyl Sulfone

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Abstract
Summary The antimalarial drug, 4,4′‐diaminophenylsulfone (dapsone) has been associated clinically with the production of agranulocytosis. A metabolite of dapsone, 4′‐amino‐4′‐hydroxylaminodiphenyl sulfone (DDS‐NOH) generates superoxide anion and hydrogen peroxide in vitro. To link oxidant injury of committed myeloid stem cells to agranulocytosis, the effects of DDS‐NOH on altering human bone marrow CFUc proliferation and in vitro reduced glutathione levels were examined in the presence and absence of superoxide dismutase and catalase. Bone marrow cells were preincubated for 60 min with either 0·01, 0·1 or 1·0 mm DDS‐NOH, washed and then 2×105 cells/plate were cultured for 10–14 d. Leucocyte colony forming unit cell (CFUc) proliferation was markedly suppressed by 0·1 mm and 1·0 mm DDS‐NOH. With 0·1 mm DDS‐NOH, addition of superoxide dismutase to the preincubation mixture further decreased colony numbers, while addition of catalase partially restored colony formation indicating involvement of hydrogen peroxide. After exposure to 0·1 mm DDS‐NOH, trypan blue exclusion by nucleated marrow cells was 98%. At the same DDS‐NOH concentration, addition of lactoperoxidase, sodium iodide and superoxide dismutase to the preincubation mixture resulted in a further decrease in CFUc proliferation. After incubation with 1·0 or 2·0 mm DDS‐NOH, bone marrow reduced glutathione levels were markedly decreased from 325 nmol/108 cells to 116·3 nmol/108 cells. Bone marrow reduced glutathione levels in guinea‐pig cells also fell after exposure to 1·0 and 2·0 mm DDS‐NOH. In turn catalase but no superoxide dismutase partially prevented the fall. Thus, these studies demonstrate that oxidant‐induced suppression of human marrow CFUc proliferation in vitro can be mediated by a metabolite of dapsone, DDS‐NOH.