Interaction of chloramphenicol and metabolites with colony stimulating factors: Possible role in chloramphenicol-induced bone marrow injury

We have recently demonstrated that two chloramphenicol (CAP) metabolites known to be produced by intestinal bacteria, dehydro-CAP (DH-CAP) and nitrophenylaminopropane (NPAP), are much more cytotoxic to bone marrow in vitro than CAP itself. Since colony stimulating factors (CSFs) play an essential role in hematopoietic cell growth, toxicity from CAP metabolites could also involve interaction with CSF or CSF-producing cells. In the present study, we found that increasing concentrations of rhGM-CSF or rhG-CSF completely reversed the inhibitory effect of CAP (2 x 10^-4 M) on human CFU-GM growth and on the growth of KG-1 cells. GM-CSF also reversed the inhibitory effect of CAP on HL-60 cells. Inhibition by DH-CAP (50% at 5 x 10^-7 M), nitroso-CAP (NO-CAP) (60% at 5 x 10^-6 M) and NPAP (35% at 10^-5 M) was not affected by either CSF. In addition to their inhibitory effect on cell growth, DH-CAP (5 x 10^-6 M) and NO-CAP (5 x 10^-6 M) inhibited CSF production by buffy coat cells 50-70% without affecting cell viability. Neither CAP nor NPAP inhibited CSF production. It is suggested that the dual toxic-inhibitory effect of some intestinal metabolites of CAP such as DH-CAP on hematopoietic cell growth on the one hand, and on CSF production on the other, renders them very potent as potential mediators of CAP induced aplastic anemia.