Suppression of in vitro granulocytopoiesis by captopril and penicillamine.
The mechanisms underlying drug-induced neutropenia are poorly characterized. We have examined the mechanism of suppression of granulocytopoiesis by captopril and penicillamine using human and canine bone marrow cells in an in vitro culture system. Addition of captopril caused no significant change in granulocyte-macrophage colony formation at concentrations up to 30 micrograms/ml. In the presence of CuSO4 (1-3 micrograms/ml), however, captopril caused significant inhibition of colony growth (p less than 0.05). Penicillamine, another agent associated with neutropenia and, like captopril, having a reactive thiol group, also inhibited colony formation in the presence of copper. Chemical congeners of captopril lacking a reactive thiol group and enalaprilic acid, an alternative angiotensin-converting enzyme (ACE) inhibitor, failed to show inhibition, suggesting that the thiol group and not ACE inhibition was responsible. Analysis of day-7 colonies (98% neutrophilic) and day-21 colonies (37% neutrophilic, 30% macrophagic, 27% eosinophilic, and 6% mixed) showed that neutrophil-containing colonies, but not nonneutrophilic colonies were inhibited by the addition of captopril plus copper. Catalase totally reversed the inhibition of colony formation caused by these agents. Direct measurement of oxygen consumption in the presence of captopril showed marked enhancement with the addition of CuSO4 and a 48% reduction in the presence of added catalase. These data indicate that drugs with a reactive thiol group can interact with copper to generate H2O2, which can be toxic to neutrophilic progenitor cells. We postulate that this may be an important mechanism for drug-associated neutropenia and a general mechanism for drug-induced marrow cell injury.
Hammond
W P
WP
Department of Medicine, University of Washington School of Medicine, Seattle 98195.
Miller
J E
JE
Starkebaum
G
G
Zweerink
H J
HJ
Rosenthal
A S
AS
Dale
D C
DC
D000818:Animals; D001853:Bone Marrow / Q000187:drug effects; D002216:Captopril / Q000009:adverse effects* / Q000031:analogs & derivatives / Q000494:pharmacology; D002374:Catalase / Q000494:pharmacology; D002478:Cells, Cultured; D003114:Colony-Forming Units Assay; D004285:Dogs; D004656:Enalapril / Q000031:analogs & derivatives / Q000494:pharmacology; D015773:Enalaprilat; D006098:Granulocytes / Q000187:drug effects* / Q000378:metabolism; D006410:Hematopoiesis / Q000187:drug effects*; D006412:Hematopoietic Stem Cells / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D007970:Leukopenia / Q000139:chemically induced* / Q000473:pathology; D010101:Oxygen Consumption / Q000187:drug effects; D010396:Penicillamine / Q000009:adverse effects*; D013438:Sulfhydryl Compounds / Q000378:metabolism
D013438:Sulfhydryl Compounds; D004656:Enalapril; C038203:S-methylcaptopril; D002216:Captopril; D002374:Catalase; D010396:Penicillamine; D015773:Enalaprilat; C046835:alacepril