Cell-specific metabolism in mouse bone marrow stroma: studies of activation and detoxification of benzene metabolites.
Two of the major cell types in bone marrow stroma, macrophages and fibroblasts, have been shown to be important regulators of both myelopoiesis and lymphopoiesis. The enzymology relating to cell-specific metabolism of phenolic metabolites of benzene in isolated mouse bone marrow stromal cells was examined. Fibroblastoid stromal cells had elevated glutathione-S-transferase (4.5-fold) and DT-diaphorase (4-fold) activity relative to macrophages, whereas macrophages demonstrated increased UDP-glucuronosyltransferase (UDP-GT, 7.5-fold) and peroxidase activity relative to stromal fibroblasts. UDP-GT and glutathione-S-transferase activities in macrophages and fibroblasts, respectively, were significantly greater than those in unpurified white marrow. Aryl sulfotransferase activity could not be detected in either bone marrow-derived macrophages or fibroblasts, and there were no significant differences in GSH content between the two cell types. Because UDP-GT activity is high in macrophages, these data suggest that DT-diaphorase levels would be rate limiting in the detoxification of benzene-derived quinones in bone marrow macrophages. The peroxidase responsible for bioactivation of benzene-derived phenolic metabolites in bone marrow macrophages is unknown but has been suggested to be prostaglandin H synthase (PGS). Hydrogen peroxide, but not arachidonic acid, supported metabolism of hydroquinone to reactive species in bone marrow-derived macrophage lysates. These data do not support a major role for PGS in peroxidase-mediated bioactivation of hydroquinone in bone marrow-derived macrophages, although PGS mRNA could be detected in these cells. Similarly, hydrogen peroxide, but not arachidonic acid, supported metabolism of hydroquinone in a human bone marrow homogenate. Peroxidase-mediated interactions between phenolic metabolites of benzene occurred in bone marrow-derived macrophages. Bioactivation of hydroquinone to species that would bind to acid-insoluble cellular macromolecules was increased by phenol and was markedly stimulated by catechol. Bioactivation of catechol was also stimulated by phenol but was inhibited by hydroquinone. These data define the enzymology and the cell-specific metabolism of benzene metabolites in bone marrow stroma and demonstrate that interactions between phenolic metabolites may contribute to the toxicity of benzene in this critical bone marrow compartment.
Ganousis
L G
LG
Molecular Toxicology and Environmental Health Sciences Program, School of Pharmacy, University of Colorado Health Sciences Center, Denver 80262.
Goon
D
D
Zyglewska
T
T
Wu
K K
KK
Ross
D
D
D000368:Aged; D000818:Animals; D001192:Arylsulfatases / Q000378:metabolism; D001554:Benzene / Q000493:pharmacokinetics* / Q000633:toxicity; D001711:Biotransformation; D001853:Bone Marrow / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism*; D001854:Bone Marrow Cells; D005347:Fibroblasts / Q000201:enzymology / Q000378:metabolism; D014453:Glucuronosyltransferase / Q000378:metabolism; D005978:Glutathione / Q000378:metabolism; D006801:Humans; D006873:Hydroquinones / Q000493:pharmacokinetics; D008658:Inactivation, Metabolic; D008264:Macrophages / Q000201:enzymology / Q000378:metabolism; D008297:Male; D051379:Mice; D016660:NAD(P)H Dehydrogenase (Quinone) / Q000378:metabolism; D016133:Polymerase Chain Reaction; D011451:Prostaglandin-Endoperoxide Synthases / Q000235:genetics / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D017154:Stromal Cells / Q000378:metabolism
D006873:Hydroquinones; D012333:RNA, Messenger; D011451:Prostaglandin-Endoperoxide Synthases; D016660:NAD(P)H Dehydrogenase (Quinone); D014453:Glucuronosyltransferase; D001192:Arylsulfatases; D005978:Glutathione; D001554:Benzene; C031927:hydroquinone