Comparative toxicity of known and putative metabolites of 1, 3-butadiene in human 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 compound in vivo or exposure of bone marrow cells to the monoepoxide metabolite, 3,4-epoxybutane, in vitro. Studies described herein compare the relative ability of putative and known BD metabolites to produce concentration dependent 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 contrast to results previously observed in mice, only the bis-oxides produced significant suppression of colony formation at potentially relevant concentrations (10(-8) to 10(-3) M). No enantiospecific differences were observed between the meso- and D,L-bis-oxides and no significant lineage-specific differences 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 in the susceptibility of bone marrow cells to 3,4-epoxybutane. Moreover, these 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. Further interpretation of these findings requires a better understanding of the metabolism of BD in humans.
Irons
R D
RD
The Molecular Toxicology and Environmental Health Sciences Program, School of Pharmacy, University of Colorado Health Sciences Center, 80262, Denver, CO, USA. richard.irons@uchsc.edu
Pyatt
D W
DW
Stillman
W S
WS
Som
D B
DB
Claffey
D J
DJ
Ruth
J A
JA
D000328:Adult; D000818:Animals; D018952:Antigens, CD34 / Q000032:analysis*; D017209:Apoptosis / Q000187:drug effects; D001854:Bone Marrow Cells / Q000187:drug effects*; D002070:Butadienes / Q000378:metabolism / Q000633:toxicity*; D006412:Hematopoietic Stem Cells / Q000187:drug effects*; D006801:Humans; D051379:Mice; D013045:Species Specificity
D018952:Antigens, CD34; D002070:Butadienes; C031763:1,3-butadiene