Comparative toxicity of known and putative metabolites of 1,3-butadiene inhuman CD34(+) bone marrow cells

Species-specific susceptibility to the hematotoxic effects of 1,3-butadiene (BD) is well known. Previous studies have revealed that murine bone marrow is uniquely susceptible to toxicity following exposure to the parent compo und in vivo or exposure of bone marrow cells to the monoepoxide metabolite, 3,4-epoxybutane, in vitro. Studies described herein compare the relative a bility of putative and known BD metabolites to produce concentration depend ent suppression of colony formation and cytotoxicity in human CD34(+) bone marrow cells. Compounds evaluated included 3,4-epoxybutane, D,L-butane-bis- oxide, meso-butane-bis-oxide and (2S,3R)-3-epoxybutane-1,2-diol. In contras t to results previously observed in mice, only the bis-oxides produced sign ificant suppression of colony formation at potentially relevant concentrati ons (10(-8) to 10(-3) M). No enantiospecific differences were observed betw een the meso- and D,L-bis-oxides and no significant lineage-specific differ ences in susceptibility to inhibition of clonogenic response were observed among early multi-potential myeloid and erythroid hematopoietic progenitor cells. The relative potencies of the bis-oxides were found to be comparable to that of the prototype hematotoxic compound, hydroquinone. These results confirm previous studies that reveal marked species-specific differences i n the susceptibility of bone marrow cells to 3,4-epoxybutane. Moreover, the se results suggest that the bis-oxides of BD are capable of suppressing the clonogenic function of human hematopoietic progenitor cells, if, in fact, they are produced in human bone marrow in significant concentration. Furthe r interpretation of these findings requires a better understanding of the m etabolism of BD in humans. (C) 2000 Elsevier Science Ireland Ltd. All right s reserved.