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Vol. 56, Issue 6, 1317-1323, December 1999
Department of Pathobiological Sciences, University of Wisconsin,
Madison, Wisconsin (S.M.H., K.H., C.J.C.); Institute of Toxicology and
Environmental Health, Technical University of Munich, Munich, Germany
(J.T.M.B.); National Cancer Institute, Bethesda, Maryland (F.J.G.);
Department of Pharmacology, University of Wisconsin, Madison, Wisconsin
(C.R.J.); and Center for Environmental Toxicology, University of
Wisconsin, Madison, Wisconsin (S.M.H., C.R.J., C.J.C.)
We previously demonstrated that murine bone marrow stromal cells
express high levels of cytochrome P4501B1 (CYP1B1) that metabolizes 7,12-dimethylbenza[a]anthracene (DMBA), and that DMBA activates the
Ah receptor (AhR) in these cells in vitro. More recently, we reported
that CYP1B1 is required for DMBA-induced lymphoblastoma formation in
vivo. In this study, we addressed the hypothesis that bone marrow
stromal cell CYP1B1, and not AhR activation, is required for
DMBA-induced pre-B-cell apoptosis. Although DMBA did not directly cause
apoptosis in pre-B cells, dose-dependent apoptosis of pre-B cells was
observed when they were cocultured with a bone marrow stromal cell
line. The DMBA 3,4-dihydrodiol metabolite was more potent in effecting
pre-B-cell apoptosis than DMBA, whereas the potent AhR agonist
2,3,7,8-tetrachlorodibenzo-p-dioxin was inactive. Both pre-B
cells and bone marrow stromal cells contained DMBA-diol-epoxide DNA
adducts, indicating that reactive metabolites were transferred from
stromal cells to pre-B cells. DMBA caused apoptosis when cocultured
with primary bone marrow stromal cells isolated from AhR-null mice but
not CYP1B1-null mice. When cocultured with AhR-null primary bone marrow
stromal cells, DMBA induced approximately 50% of the pre-B-cell
apoptosis seen with stromal cells from AhR-heterozygous mice. This
reduced level of apoptosis parallels the decreased CYP1B1 expression in
AhR-null mouse bone marrow stromal cells. These findings provide
convincing evidence that bone marrow stromal cell CYP1B1 metabolism of
DMBA, but not AhR activation, is required for DMBA-induced pre-B-cell apoptosis.
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