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Vol. 56, Issue 6, 1317-1323, December 1999

Bone Marrow Stromal Cell Cytochrome P4501B1 Is Required for Pre-B Cell Apoptosis Induced by 7,12-Dimethylbenz[a]anthracene1

Shawn M. Heidel, Karrie Holston, Jeroen T.M. Buters, Frank J. Gonzalez, Colin R. Jefcoate, and Charles J. Czupyrynski

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.

Copyright © 1999 by U.S. Government


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